DAIJ

Go through this process, writer will be more understand the messages that the author or artist want to convey. In addition, DAIS is actually more to the writer opinion and It can help writer to improve thinking skill from different angles. In DAIS, we no need to create anything and it only need a short of time to write DAIS. On the contrary, design thinking is a process create something that based on our client's opinion, benefit, requirement and condition. The whole design thinking process include empathic, define, ideate, prototype and test.In this process, we need to do a lot of research to collect information before we start designing, for example, observation, interview, survey, analysis data and etc. It will take longer time for the whole design thinking process, because it need times for gathering data, analysis data, brainstorm idea, testing and experiment. In conclusion, DAIS is based on writer own opinion and a process to understand creator message. On the other hand, desig n thinking is based on our clients benefit and requirement. These are the differences between DAIS and design thinking. ) When would you use DAIS and when would you use design thinking? When want to gather some information about artwork or images, I will use DAIS. Because DAIS is simple and suitable to collect data from artwork or image and an understand the artwork in details. When have my own clients who need me to help them solve their problem, I will use design thinking. It is more suitable to understand the need and the way to help my client. C) How are they related? Visualize the relationship graphically. The above image is about how DAIS related to design thinking.The design thinking process is created based on â€Å"the Right Brain initiative† website and then I add the DAIS between â€Å"empathic† until â€Å"prototype†. From my understanding DAIS is included in between empathic until prototype. It start with empathic; collecting data like description i n DAIS, understand our clients and the market trend. Then, define which is analysis the data we get, think from different angle to understand deeper. After that, follow by ideate, it's like interpretation from DAIS. From the view of designer, create something that can related to our clients product, means how to relate our own idea to clients product.Lastly is prototype, present our idea to the clients, try to convey and allow them to judge see whether the idea is suitable for them or not before experiment. This process is like judgment from DAIS. In conclusion, DAIS and design thinking is actually related to each other. Both also have their own advantages and both also can support each other. By using two method at the same time, can make the process more clear and easy to understand. 2. We have discussed a number of problems that needs to be addressed e. G. Single parent, homeless.In one of the tutorials, the different problems faced, research questions, hypotheses and proposed so lutions for single parents was discussed. Would DAIS or design thinking help you to identify better solutions? Why? Yes. DAIS or design thinking have their own step to find out the answer. By following with these step can help me understand and identify he problem easily. Furthermore, these steps can guide and improve my point of view of the problem. For example, we can use different angle to think and to solve the problem. 3. Based on the above, what does Picasso quote on research mean?What does having your own voice mean? Why do We need to acknowledge the source? What would you define as original? Based on the my research, Picasso quote can be define as art-based research can be defined as the systematic use of the artistic process, the actual making of artistic expressions in all of the different forms of the arts, as a primary way of understanding and examining experience by both researchers and the people that they involve in their studies. From my understanding, the word †Å"research† can define as experiment.Picasso explore himself by using art, he using painting to experiment the changing of the color and technique, and how it can change the element and the feeling of the whole painting. As a designer, we are not just sitting there and read data, we always need to experiment different kind of technique to gain knowledge and experience. This is what I understand from that quote. Having my own voice can be define as to stay strong and believe of my own pinion, to adhere my own decision, to speak out what I want to say or have my own freedom. The word â€Å"voice† can represent idea, choices, decision or freedom.For example, a boy making decision on what to study for degree, parent always hope he can go study as doctor, account or some others career that can earn a lot of money, the boy will choose the subject that he is not interest in, it is because the boy do not want to disappoint to his parent. In this situation, the boys voice being cover by his parent voice and he choose to listen his parent voice rather than his voice in his inner heart. We should rye to listen and believe our own voice, because this is our life. Speak out is the only way to get what we really want and what we really need.Based on my research, there are few reason that why we need to acknowledge the source. The first reason is to avoid plagiarism. Since we are borrowing people's facts or document to prove our research, we should be honest to give them credit to prove that we are borrowing their document and not stealing. The second reason is allow reader to know furthermore about the source of material we use. This not only can convince them, but also can help them understand more about what they interest in. The third reason is to enhance our credibility as a writer or researcher.To show how serious and important that this research to us, for example our research subject, objective, argument, ideas, experiment and so on. These are the three main reason that why we need to acknowledge the source. Original can be define as not only new but the very first or one of a kind. From my understanding, original means some object, thing that created by ourselves. It also mean the beginning of something. For example, as an artist, use to create my own anima character when I was free. I will get some references about how my character should act like.Let's say my character are standing, then I will follow those standing reference for my character. The output would be different because with my own art style it will look totally original by me. 4. What have you learnt from the exercise on abstraction? From the abstraction question 1, I had learnt how to think differently and see things from different angle. The meaning and message will change when we change another angle to understand the problem, it can change the tone of our thoughts from negative to positive. This is how those successful people thoughts.For example, create a AD vie w of the word â€Å"HI†, below is the image. As you can see, there are different be;men a, b, c, and d; a is opposite of c, the shape of b and d is same, but b is red color and d is black color. This show that a tiny changes will always bring different. Just like what Richard Bach said â€Å"A tiny change today brings a dramatically different tomorrow'. This is what I had learnt from the abstraction question 2. From the abstraction question 4, there are 2 different things that I learnt when I created an abstract kaleidoscope pattern; one is from Photos, another one is from Sony Vegas 13. . In Photos, I had learnt how to find he Photos tree brush to help me reduce the time on design the abstract art. Then, adding some sketches and TV noise effect on my abstract art. In Sony Vegas 13. 0, I had learnt how use front and side mirror effect to reflect my abstract art. After I reflected it, I added glowing light effect to make it like moving. In last step, is to change the color by using color correction. In my conclusion, had gain new knowledge from abstraction question 2 and 4 which are â€Å"think in different angle† and â€Å"some technical knowledge† in Sony Vegas 13. And Photos. 5. We have also discussed in 3-4 tutorials, what factors would attract the argent audience's attention and leaves them with a wow feeling. Identify these factors and how they are achieved from: a) The activities related to the handout on self-promotion In self-promotion section, we are requested to create a magazine cover that can convey message to the audience. My group are created a magazine cover about Christmas. We separated few step to achieve our goal.First, is to observe competitor's magazine cover, to analysis how they create the magazine, in what kind of style. From our observation and analysis we noticed that most of the Christmas magazine cover is more to the realistic ND warm feeling image. It looks normal and a bit boring with this kind of style, there fore we decide to change it to illustration style. We arranged different kind Of item to form a red Christmas tree on a simple white color layout to catch people attention from different kind of magazine. The spacing and color will emphasis the red Christmas tree.Our objective is to bring back audience childhood's memory and to convey audience to celebrate Christmas with their family. In this section, we learnt how to use the correct art style to promote the product and use the right image to convey message to audience. ) The activities related to the handout on brainstorm (for our clients) In brainstorm section, we are requested to help our client to solve their problem. My group are help a fashion customer to promote his new fashion brand named â€Å"SPACE†. At first, We are trying to understand our client company and his competitor.Then we will discuss with him about his requirement on promoting the brand, such as budge, printing media promotion, location of the printing m edia, the style of promotion, TV advertisement promotion, discount and etc. Based on the data we collect, we will try to search the related information and get some inspiration to create a ester. Based on this section, we learnt how to communicate and handle our client. It is important to do some survey or interview to our client, because sometime our client do not tell us what they really want or need, they confuse and do not understand what kind of information that graphic designer need. . What do you think fun, sustainable design and interactivity mean? Fun, sustainable design and interactivity can define as something that not only can entertain user, but also can deliver the message to user in creative way. With these fun, interactivity and sustainable design, will leave deep impression in the audience mind. User will remember it forever. For example, a horror website game named ‘the house†, this game is created by SHANGHAI. The house is a Flash horror point and clic k games. Player can experience the scary feeling in horror house by just clicking the item in rooms.It is fun and interesting. Remember the first time I play this game is in high school, it really leave me deep impression, until now I still remember this game. In conclusion, a design that include fun, interactivity and sustainable design will always leave deep impression for the audiences. 7. What have you learnt from the various topics covered in the syllabus? Elaborate on three which have impressed you the most. DAIS, design thinking and the process of creating an abstracting art is the things that had learnt.DAIS is one of the method that similar to the previous critique method that I learnt in History of Art. As method before in the question 1, DAIS is a process to gather information and collect data from critique artworks, images or photos. It includes description, analysis, interpretation and judgment. The reason why remember it is because we have discuss DAIS for few times an d we have use DAIS method to solve problem. Design thinking is the second method that always being discuss in lass or compare with DAIS in exercise.I had used this method for my final year project, it is very useful and it guide me a way to solve some of the final year question, therefore it leave deep impression for me. The third thing I learnt in this syllabus is creating abstraction art. The reason why it impressed me the most is because had created an abstract artwork by using Photos and Sony Vegas 13. 0. The process when creating that kaleidoscope pattern is really fun and enjoy. Experiment different effect like changing the color, adjusting the glowing lights effect and editing mirror affliction, this process is like expressing my feeling in art.As a designer or a creator, We should enjoy the process on creating something rather than outcome. In Bruce Man's quote, he mention that â€Å"Process is more important than outcome. When the outcome drives the process we will only ev er go to where we've already been. If process drives outcome we may not know where we're going, but we will know we want to be there. † In my conclusion, DAIS, design thinking and the process of creating an abstract art are method and technique skill that I learnt in this syllabus. Both method an be used in any others subject and can use it to solve the problem in future.

Mega Trends in Fashion

T4 MEGATRENDS 1. Celebrity Culture: Celebrity culture means that common people want to look and feel like celebrities. This affects a shift in consumer behavior and marketing. People are more likely to purchase garments if celebrities are seen wearing them than the consumers’ personal taste. This new celebrity obsession will drive consumers to buy the latest worn garment their most admired celebrity is wearing. This change in consumer behavior will have to be taken into consideration when companies advertise as they will be more likely to sell a product if celebrities are used in the advertising campaign rather than a ordinary model.Celebrities are influencing design, advertising and distribution. 2. Social networking: Social networking is the fastest growing trend. Most the population are engaged in some sort of social networking whether it be facebook, twitter, pintrest or blogs. Due to social media, word-of-mouth promotion is a new phenomenon, which can either have positive , or negative outcomes for companies. The constant sharing and use of images/ideas/technologies means less promotion and marketing is needed by companies to distribute their products.This is the case as everyone has instant updates and access to the latest trends. Companies do not have to exert their effort into promotion, as consumers are already in the know. 3. Global Financial Crisis: Due to the current financial issue, many people are left unemployed and redundant. Many people have had to re-budget and re think their expenditure. Many people have had to restructure the way their families live and have had to cut down on many unnecessary expenses.Fashion is one of the first categories that people cut down on. Food and housing are seen as essentials and fashion is seen as a luxury. Thins being the case, people don’t have the money to buy and spend, making it difficult for fashion houses to remain open as they have a dwindling clientele. 4. Satiability: Sustainability and th e environment have become most topical in todays world. With this knowledge, consumers want more company transparency.Consumers want to be aware of the origins of their purchases as they care about human rights and the environment. Consumers want to be able to reuse and recycle clothing. The notion of vintage clothing has become very trendy as consumers realize that old clothes are still wearable and are of quality. The notion of fast fashion is disturbing the environmentally friendly consumers, as high levels of waste are prevalent. Companies are being forced to reassess the ethics of their sourcing, manufacturing and distribution processes.

A Business Trip to Chile Essay

Excited about visiting a South American country for the first time, I started my journey to Santiago De Chile from Miami on March 2nd, 2012. To start with, I was skeptical about the quality of a Chile based airline. But, I was amazed by the excellent service provided by LAN airlines. My perception about a Chilean company changed then and there. Also, prior to my flight I doubted whether the officials in the flight will understand English (even though we were assured by the Professor that there wouldn’t be language problems during the travel) and my doubts didn’t fructify. In fact, the quality of the food given to us in the plane set up a high expectation for my one-week long stay at Santiago. Day One After watching the Pirates of the Caribbean – At World’s end, a movie which I have been craving to watch for a long time, and a couple of hours of pleasant flight, we landed in Santiago on time. As soon as the automatic door swung open letting me in to the airport, I noticed a group of people standing before a counter that was used to collect a reciprocity fee. The notice board before the counter showed â€Å"US – $140†. As I didn’t fully understand what a reciprocity fee is and since I was coming in to the country from US, I stood at the back of a very short line counting my $140. When my turn came, I was pleasantly surprised to find out that it applies only to US Citizens and that it is a one-time charge only for the life of the passport. I wondered what the reciprocity fees was and later found out that this was the amount the US charges Chileans entering the country. For that reason, the fees are referred to as â€Å"reciprocity†. After a little research, I found that out of the countries in South America, five of them charge a fee: Argentina, Bolivia, Brazil, Chile and Paraguay. The fees charged are in direct relation to what the home country of the passenger charges residents of the country you are visiting. The fees look like a good source of revenue for these countries. I reached the Atton El Bosque hotel by hiring a taxi from the airport after a little struggle to explain the hotel name and location to the taxi driver. After resting for a while, and after a brief orientation meeting, we started a City Tour. The tour guide who accompanied us was very knowledgeable about the history and culture of Chile. It was a pleasure to see the La Moneda Presidential Palace and was interesting to learn about the history of the palace. Construction of the La Moneda started in 1784 and was constructed to be the country’s official mint, hence the name which translates to The Mint. A wiki entry shows that coins were minted from 1814 to 1929. And, in 1845 the palace became the residence of the president. I learnt an important history of Chile that day about the Chileans having a different 911 to remember about and that was about the military coup d’etat on September 11, 1973. The then Commander-in-chief Augusto Pinochet led the coup against the President Salvador Allende. Despite the air raids and ground attacks on the palace, the President vowed to stay in the presidential palace and rejected the military’s ultimatum to step down. Eventually the President killed himself (although this is questionable and still under scrutiny). The tour guide explained this really well to the group and pointed to a closed door, which was guarded by a uniformed officer, mentioning that the dead body of the president was taken out through this door. After finishing the tour around the palace, we had a stop at Los Dominicos for some artisan shopping and then the first day of the trip officially ended. Later for dinner, we went to a place nearby the hotel and the service was not so good. So we decided to tip him lesser than the 10%. But to our surprise, the waiter stood there demanding for the remaining tip. We didn’t know if it was a Chile culture to tip 10% mandatorily. Later I found out that the livelihood of most of the waiters depends on tips. They may get a minimum salary but it is barely enough to cover transportation. But according to me, the financial dependence on tips doesn’t necessarily mean the waiters/waitresses deserve to get tips for a lousy service. Thus, day one ended with some important lessons learnt about the history and culture of Chile. Throughout the trip we were informed of the importance of the copper industry to the economy of Chile. Day Two We started early on day two for a two hour long trip to the port city of Valparaiso. En route to Valparaiso, the second largest city of Chile, we stopped at a place to refresh ourselves and we saw some Llamas at the back of the store. It was the first time I saw a Llama. Later on a casual talk to one of the hotel staff, I learnt that during the Spanish conquest the Llamas was primarily used to bring down ore from the mines that were atop mountains. But then the introduction of horses and donkeys diminished the importance of Llama as a beast of burden. And, that they are primarily used as a source of food and fiber now. The first thing that came to our attention in Valparaiso was the National Congress of Chile. Our tour guide pointed out that Pinochet shifted the congress from downtown Santiago to Valparaiso. The Chile government, like the USA, has a bicameral legislature. The legislature is made up of the Chamber of Deputies, which is the lower house, and the Senate. Also, we saw the Valparaiso market through the windows of the bus and the guide mentioned that you will get all sorts of stuff (even used goods) at cheap prices in that market. Chile has two Nobel Prize winners and both awards were in the fields of Literature. Our tour itinerary indicated a visit to the house of one of the Nobel laureates, Pablo Neruda. I wondered whether there will be anything interesting to see at a house of a poet. Again, my perceptions turned out to be wrong after entering the house and after listening to the narrations (in English! ) through an audio guide. I liked the way Pablo named everything in his house. And, the view of the port from his window was stunning. Then we trekked down the streets of Valparaiso and walked by the beautiful houses. The guide showed us certain parts of the town overlooking the port that were occupied mainly by the English and a church which had service in German. Later we took a short ride on a funicular, which was used to take the residents up and down the steep hill sides of Valparaiso. The funiculars are now operated just for tourism purpose as the cheap fee that was being charged previously for routine use was not profitable for the operators. Anyhow, it was interesting to ride on a historic means of transport. From there, we proceeded to have lunch at a wonderful restaurant overlooking the sea. The founder of La Bicicleta Verde greeted us during lunch and gave us an introduction to his business. His company, which gives a bicycle tour of the city, was founded with a local partner and through InnovaChile, CORFO, which is the executing agency of government policies in the field of entrepreneurship and innovation. His insights about doing business in Chile were really thought provoking and his discussions revealed the support from the government for such innovations. After that, we took some time off walking along the beach and under the bright sun and then returned to the otel. The second day too was filled with lessons about the culture, business in Chile and about the wonderful poet, Pablo Neruda. Day Three On the third day, we visited the Adolfo Ibanez University that was atop the scenic San Ramon Hill. The University was away from the city and the tour guide told us that many poor people live near that college. Thus, students have been skeptical of travelling to the college as there have been many incidents of robbery. Anyhow, we reached the University from where we could see the whole of Santiago from the hills. There, we attended a lecture from Guillermo Paraje, one of the eminent professors of the University, about the Latin American Economies. The lecture started off with the information that the Latin American countries were only mildly affected by the economic crisis going on around the world. Also, the unemployment rate has been going down along with an increase in the average wage. Most importantly, the increasing price of copper has boosted the growth rate of the Chile economy. The Professor took pride in mentioning that Chile is the first South American country to be an OECD member. One important point that the professor touched upon was the low productivity of labor. He compared the productivity of Korea and Brazil and his graphs showed that Korean has been growing its productivity rate at 4. 7% whereas Brazil has been growing only at 0. 1%. This trend was seen throughout the Latin American countries and is a growing area of concern. Also, the Latin American countries were lagging behind in the service sector. Moreover, there seems to be an increasing gap between the rich and poor. He raised an important point about Chile (or Latin American countries) remaining as a producer of raw materials alone. That is, he mentioned Chile is the leading exporter of copper but it is not a good producer of finished goods based out of copper. This, according to the Professor, should be the long term strategy of all Latin American countries. A casual talk with the Professor after the lecture revealed that Chile is not investing much in renewable and nuclear energy. A recent proposal to invest in nuclear energy was rejected by the Government citing safety issues, especially after the incident in Japan. Being a growing country, Chile could encourage more people to invest in renewable energy. After that, we toured in and around the University and then returned to the bus to be greeted by our smiling bus driver who always referred to us as â€Å"Macho, macho†. Later in the day, we had a presentation about Flora & Fauna Chile Ltda. (Ltda. stands for limitada for limited companies). The mining industries cause a lot of environmental issues and the activities around the mining have an impact on the wildlife around the region. The company does a wonderful job in minimizing the impact to the habitat. The government made it mandatory for these mining companies to get the advice of Flora and Fauna. I was happy to learn that the government is actually interested in preserving the habitat of the various regions and they were assisted by this wonderful set of people who work for Flora and Fauna. Then, we had a presentation from the Managing Director of Banco Santander. The Banco Santander is the leading bank in Latin America. He gave as some good insights about the financial system in Chile and told us that the financial system of Chile ranks among the best in South America. Also, Mr. Martin Perez, described the Pension System of Chile. A reform in late 1980 replaced the pay-as-you go regime with a fully-funded pension system. The third day was filled with lessons about the economics and financial systems of Chile. Day Four The next day, we visited the Frito-Lay, which was located in Cerrillos. The manager of the plant addressed us with some information about the plant. In Latin America, Frito-Lay has 6 production sites and the Cerrillos plant was bought in 2008. One of the slides of the presentation showed a growth rate of around 8% in the volume of sales and a 15% increase in revenue since the inception of the plant. Another graph illustrated a volume of the salty snacks portfolio of Frito-Lay despite having no new line in the site. The manager mentioned the increase was because of an improvement in the efficiency of the site. The manager takes pride in the fact that they have a world-class site in terms of efficiency, service and sustainability. For instance, the plant includes a series of photovoltaic panels on top of the factory that produces around 12KW of electricity. Interestingly, the plant has reduced its water and energy consumption significantly. Also, the future plans for the site includes a reuse of 100% of the wasted water. Once the presentation was done, the manager took us around the factory and showed us the various lines and packaging units. Along the way, he told us that the potatoes are grown under controlled conditions and that it is not the same as the ones used for domestic consumption. On inquiring about some froth lying on the ground, the manager told me that it was the result of an experiment to re-use the starch produced from the potatoes. This was really surprising. Apart from being very sustainable, the company was trying to innovate in various ways. Finally, on inquiring about the software system used in the plant, the manager informed me that they are going to switch to SAP in few months. The plant was going all the way to become very efficient. It was very impressive. After a delicious lunch, we visited CORFO Chile for an introduction to Start Up Chile. This was the most interesting site visit for me. The Start Up Chile is one of the best incubator programs designed to attract entrepreneurs from across the world. It was started by the Chilean Government to convert Chile into an innovation and entrepreneurial hub of Latin America. We were presented with the ways in which an entrepreneur is selected for the program. Apparently, an expert team, including eminent people from USA, selects the best among the applicants. It was also interesting to know that the program has attracted people from India and China and that too, with minimal advertisements in those areas. Through the Start Up Chile program, entrepreneurs work on their projects at Chile and are reimbursed up to $40,000 in cash. During 2011-2012, the program has attracted people from diverse industries including IT, e-Commerce, Energy, Cleantech, etc. The basic idea is to boost the confidence of the local entrepreneurs by sending a message that Chile supports such innovations. The incoming people are also required to earn around 4000 points to successfully complete the program. They earn points in various ways, including giving seminars to local universities and thus, they add value to Chile. I believe this is an amazing idea to boost the economy of a country which is presently dependent on only exports of raw materials. They are building a future which is not necessarily dependent on the export industry and thereby, Chile is on track to building a sustainable future. Day Five We visited the factory of Agricom, suppliers of fresh fruits, on the second last day of our tour. Not surprisingly, the USA is the biggest market for avocados, which are exported from this facility. The company also offers other fruits such as: Grapes, Drupes, Oranges, Apples, etc. Also, Agricom generates more than 2000 jobs for the Chilean labor market. Europe is also an important market for Agricom. As future plans, Agricom is planning to invest in walnuts. The factory visit was very informative and we could feel the urgency with which the workers go on with the various activities. The urgency can be directly attributed to the freshness factor of the fruits. Then, we visited Kross, a microbrewery factory. The founder welcomed us and took the pain in explaining to us the whole process of brewing the beer. On asking whether the recipe can be easily replicated, Mr. Asbjorn explained that he can write down the recipe and give it to me but, it will be very difficult to replicate the same taste as he has the right equipment. He also mentioned that it is not a good business sense to copy another beer. I felt it was a valid point and I learnt an interesting lesson. We, then, had an amazing barbeque lunch at a picturesque building at Vina Mar, which is a famous vineyard in Chile. Later, we visited another wine factory called the Vina Quintay and the Commercial Manager of the company guided us through some wine tasting. Day Six On the final day of the trip, we had the most important topic as presentation – Mining in Chile by a senior official from Kinross, a Canadian gold company. Starting up with some basic facts about Chile, the Vice President informed us that the corruption in Chile is really low and doing business in Chile is very easy. He goes on to say that 28% of the world’s copper reserves are in Chile and that Chile’s economy is heavily dependent on mining. The mining, he said, is concentrated in the northern parts of the country. The work force in Chile is well trained for the mining business and thus makes this an important factor for investing in the mining industry. Chile is the world’s largest producer in copper. They also produce gold and Chile is the 13th largest producer. Interestingly, Chile is the largest producer of Lithium and the fifth largest producer of Silver. The mining industry contributes to 22% of the GDP and 60% of the exports. The mining industry directly employs around 70,000 people and indirectly employs more than 300,000. The Vice President goes on to say more on the challenges faced by the mining industry which includes the dwindling capacity of water, increasing demand for energy, increasing demand for specialized labor and so on. The trip ended on day six after the Kinross presentation. Departure Thus, I prepared to leave Chile after a wonderful trip with wonderful people. I probably learnt a lot of things about Chile in this short trip than I would have learnt if I had read through a book about Chile. I learnt a lot about the economics, the importance of the mining industry, the rich history and culture of Chile, the stable financial system, etc. Experiencing the culture was really important and if I start a business I would definitely look at Chile as the first option. Final lesson: if you pay your room rent and other expenses at the hotel with US Dollars you don’t have to pay sales tax.

Legal Aspects of Hospitality Managment Term Paper

Legal Aspects of Hospitality Managment - Term Paper Example The safety regulations require the employees handling food to observe personal hygiene and use clean uniform and other attires when handling food. In addition, all food handlers are required to undergo medical check-up on a regular basis in order to minimize the spread of contagious diseases such as tuberculosis and diarrhea. The restaurant managers are required to maintain clean and safe environment and premises in order to reduce liabilities that business may incur through injuries to visitors while in the premise (Tansey and Rajotte 79). If the restaurant management complies with these safety requirements, clients will get motivated and encouraged to revisit the restaurant in the future. 2. Improved workers efficiency Safety standards require restaurant owners to ensure secure and clean environment of the business. Another requirement is better working environment for employees and the use of recommended food handling facilities (Brown 785). Regarding the safety of the workers, th e law protects employees against discrimination, poor working environment, and unfair dismissal from work, inadequate pay including overtime allowances, leave and other allowances. If the business is able to comply with these requirements it will motivate employees and increase their productivity (Jha and Elgar 51). Also, employees feel motivated because of better pay, appropriate equipment and excellent working atmosphere and they are able to identify with business. 3. Reduction of unhealthy competition When establishing a restaurant the investor must ensure compliance with all legal requirements relating to safety of the customers, workers and the environment (Vogel 116). The law requires the restaurants to ensure the food is... This paper approves that food safety rules describe the hygiene conditions for handling food and the environment surrounding the food business. The process involved when interacting with food safety rules is usually cumbersome and cost intensive. The process of registering business is generally tedious and time consuming. Some businesses are unable to meet the safety regulations requirements hence they opt out of business. This closure of business results to significant loss of business revenue during the closure period. This essay makes a conclusion that the future of the restaurant business lies on the level of compliance of the business with safety regulations relating to customer, employees and the environmental protection. The safety standards have stringent requirements for the establishment and management of the restaurants. Adherence to these safety measures will promote business growth by increasing customer satisfaction and loyalty. Also, this will increase the efficiency of business through the use of recommended food handling equipments, protection of environment against improper waste disposal and will result to motivation of employees as a result of better terms of work. However, many potential investors may not comply with these standards hence reducing the potential for investment. In addition, the high cost of business compliance with safety regulations will reduce business revenue hence decrease employment opportunities.

Audiometry Lab Report Example | Topics and Well Written Essays - 500 words - 1

Audiometry - Lab Report Example The conduction testing of the air presents stimuli to both ears but independently using some special earphones. The stimuli is reduced while going from the test ear to the cochlea of the others ear. This is energy loss is known as the interaural attenuation which ranges between 45 – 80 dB. However, stimulation occurs to the cochlea in both ears. As a result, cross hearing is a situation to consider more in the conduction of bone than in the conduction of air (Yoon et.al 469). The mastoid process of the proper ear is used to transmit pure tones by placing vibrator bone over it. The results of the experiment may be determined by the placement of the vibrator as well as the pressure. Technical factors and distortion may cause may limit the output of the audiometer to about 80 dB. The non-test ear should always be eliminated from the procedure whenever the cross hearing is suspected. In order to remove the non-test ear from the procedure in case of any suspected cross hearing, is to mask by delivering noise to the non-test ear (Yoon et.al 469). The loudness of the masking procedure should be able to prevent the tone reaching the non-test ear and stimulating it. This experiment aims at determining the threshold hearing over a variation of frequencies. The experiment may test the bone conduction also known as the vibrator as well as the air conduction or the loudspeaker. But the audiometer can only test the air conduction also known as the loudspeaker. The procedure of performing the experiment was the same for two different partners. The first thing was to check and confirm that the connection of the audiometer and the headphones was not loose. The experiment was conducted in a silent laboratory. My partner put on the headphones while I adjusted the volume of the audiometer over the required frequencies. The hearing threshold was determined for every frequency. The button was used to

Working Groups and Teams Essay Example | Topics and Well Written Essays - 500 words

Working Groups and Teams - Essay Example Within that group, teams may be formed to achieve specific tasks in the way of achievement of the overall goal of the group. Group is a larger term as compared to a team. Another fundamental difference between a group and a team is that individual members of a group do not need to have concern with the achievement of the other members of the group whereas people forming part of a team have concern with and are affected by the performance of other members of the team. Challenges of communicating in a team are more than those in a group. Groups normally have a well-established and organized system of communication. There is a process through which message is conveyed and received, e.g. through emails or letters. The challenge of communication in a group is that it is more time consuming as compared to communication in a team. For example, let’s suppose the member of a political group writes a letter to the chairman of the party. The chairman might take long to reply. On the other hand, people working in a team are generally in constant connection with one another. Even if they are working separately at different places, they communicate through cell phones. Since the performance of one team-member affects that of all others, team-members are concerned to maintain constant contact with one another. However, communication in a team is very challenging since the team-members develop friction among one another while constantly working together. â€Å"Conflicting goals can quickly turn into personal dislike† (Mind Tools, 2012). Team members become agitated, develop attitude problems, and enter into dysfunctional conflicts. These team members avoid talking to one another and if they have to, there is always a risk that the conversation might end up in an argument. Effective collaboration within teams is more difficult to achieve as compared to the groups. The leader of the group can generate a

Talking Bacteria Assignment Example | Topics and Well Written Essays - 250 words

Talking Bacteria - Assignment Example n exploit this ability of the bacteria to develop drugs against the toxin as they could understand, the formation of quorum is the right stage when the bacteria produce toxins. Quorum sensing initiates the release of toxins by bacteria for instance, V. cholerae. Every bacteria has its own autoinducer, to communicate with its own kind. This is a signalling process which aids in bacterial communication to aggregate, to form a quorum, to perform their function. 3. Basic scientific research that explores the answers to questions with no practical goal in mind. Some politicians and taxpayers are opposed to spending tax dollars on basic research because such research has no obvious practical application. How does the basic research leading to the discovery of quorum sensing in photobiotic marine bacteria help justify the expenditure of taxpayers’ money? Basic research is the basis of all the advanced research. Quorum sensing enabled one to understand that bacteria do communicate through signalling pathway either to release toxin or to perform some beneficiary role. This signalling resulted in aggregation of bacteria and they bioluminescence only when they are close to each other, indicating that they are going to perform some imperative role. This basis enabled researchers to understand the nature of microbes, production of antibiotic/ toxin and helped researcher to develop drug. Each bacteria has its own autoinducer molecule, for instance, Gram-negative bacteria such as Pseudomonas aeruginosa use different versions of AHL molecules (acylated homoserine lactones) to communicate while Staphylococcus aureus use peptides. These autoinducer molecules are signal molecules which help bacteria to aggregate or form quorum, as after forming quorum they produce toxins. 5. Many types of animals that live in the depths of the ocean – where there is no light from the sun – have light-emitting patches. Scientists have discovered that these patches contain glowing bacteria;

Price Analysis for Navigation System Assignment Example | Topics and Well Written Essays - 750 words

Price Analysis for Navigation System - Assignment Example Thus, the forecast of the price mainly depends on the price comparison of the competition taking into consideration that this company offers a similar service of the mine. Navigation system fundamental information entails grouping presentation industry chain configuration, which mainly encompasses international analysis, local market breakdown, macroeconomic situation and corresponding economic condition analysis (Murphy, 2009). Moreover, navigation policy and plan in regard to the underlying navigation system product depends on the specification, manufacturing process and underlying cost structure. The fundamental manufacturer of the navigation system volume manufacture cost price, income manufacture worth gross information and corresponding navigation system volume manufacture marketplace share mainly dictates the underlying market share supply demand import export consumption. Navigation system volume manufacture value cost mainly revolves around the value gross margin information. The concepts allowability, allocability and reasonableness in regard to the cost of the navigation system of the Navo tech mainly addresses directly the prevailing legitimacy of the cost charged against the corresponding cost charged on a particular research cost award (Murphy, 2009). Thus, the process of determination of the allowability, allocability and corresponding reasonableness of the prevailing expense is majorly based on particular guidelines of the federal cost principles. Moreover, it is will be dictated by the office of the management and budget of the Navo tech. Reasonable costs are the prevailing price that is normally consistent with the cost a reasonable individual would pay in the similar conditions for the navigation system to the same company producing similar product. Allowable costs are the ones that are utilized in the connection of the navigation system. It is the cost incurred under the budgeted agreement and mainly benefits the

Un Decided (Can be chosen from 6 topics in the handout uploaded) Essay

Un Decided (Can be chosen from 6 topics in the handout uploaded) - Essay Example 17). Thomas Hobbes, John Locke and Jean-Jacques Rousseau talk about the social contract because man lived in a State of Nature and the social contract serves as the gateway to the civil society. It is important to note that three philosophers have their distinct view of the state of nature and have made their contribution to the social contract theory, but all share these principles. The social contract theory by Thomas Hobbes deviated from the above views which were major proponents of theories by John Locke and Rousseau hugely influenced by his views on the state of nature (Markfield 2006, p.35). Hobbes advanced for a more power vested in the government because of his views that humans are generally selfish seen in salvage in the state of nature before civilization or civil society The main aim for this essay paper is to address the question of what is the role of social contract in western political theory. The objective of this essay paper is to list each role of a social contract and give an in-depth explanation as to how it is a role in relation to the western theory of politics. It will give a brief introduction and understanding of the theory of western politics. The theory of social contract originates from the concept that the society needs just as well as the need for a just people (Huttegger and Smead 2011, p.15). With a keen look at the works of Jean Jacques Rousseau, Thomas Hobbes and John Locke, this essay paper intends to give a clear perspective on the role of social contract in western political theory. The basic understanding of a social contract is to create a voluntary contract. This contract helps the society to shift from a state of nature to a state of civilization. The term â€Å"state of nature† is similar to the operating of the animal kingdom. It is important to note that the security of a person is very much dependent on the person’s power. Social contract strives to provide a

Fukushima Nuclear power in Japan Essay Example | Topics and Well Written Essays - 500 words

Fukushima Nuclear power in Japan - Essay Example The Japan government decided to close all nuclear power plant projects in Japan so as to prevent repetitions like that of Fukushima in future (Straight). Japan managed to get an alternative source of energy to supply the needs of the country through buying of liquefied natural gas from Russia. Following the nuclear disaster, many people working in the reactor plus the surrounding environ got exposed. In addition, the environment around the reactor also got contaminated posing considerable risk. In regard to human exposure, a number of children living in the environs of Fukushima became recently discovered to be developing abnormal thyroid lumps (Straight). Exposure to radiation posed a risk of development of poor health outcomes in the given population. The government of Japan in trying to come with the solution to that given problem, food stuffs like exported rice from that region got scrutinized for radiation exposure levels so as to limit the spread of radioactive contaminants to other countries (Straight). Also, faced with the problem of human exposure, the government somehow managed to have evacuation and resettlement plans in action. With the environ around the Fukushima becoming unsafe due to the high radiation levels, the Japan government opted to resettle individuals that lived around the reactor in another place fit for human settlement. In addition, some of the workforce that worked in the Fukushima nuclear reactor, became not allowed to work in other nuclear reactors following having radiation levels higher than required. Such a means by the government ought to protect humans from overexposure from radiation (Straight). After the Fukushima nuclear disaster, the problem of controlling leakage of radiation emanated. Environmental leakage could only be minimized through proper destruction of the nuclear station plus proper disposal of the radioactive substances. The wrecked

Film journal Essay Example | Topics and Well Written Essays - 1250 words

Film journal - Essay Example The experience comes over a period, and it is born out of creative and the technical expertise, and above all the love for the job of film production with the ability to choose the right talent. For a film to be able to realize itself, the producer will have the responsibility of assessing the film to ensure it is to the expected level. He will tend to the film from the time of conception to the time it will be completed. The producer will serve as the organizer of the film, and he will provide a good environment so that the entire team that is involved in the production of the film can flourish for the good of the film. Most films made in Hollywood the producers are the decision makers during studio system. This is because they supervise a variety of films at the same time, controlling the stories, the budgets and the overall production taking care of each aspect of the production on a whole, thereby being responsible for the fate of the entire films. Producers are responsible for t he development of ideas, and once they are attached to the idea, they put around the right team and go ahead to supervise the entire functioning. For instance, Irving Thalberg, who was once famously involved in over a hundred productions. David O. Selznick, the producer of ‘Rebecca’ was instrumental in bringing Alfred Hitchcock to Hollywood to direct the film because of Hitchcock’s expertise with thriller-suspense cinema. Hitchcock took charge of the film and was so good with his work that Selznick famously said that the only director he can ever trust a film with was Hitchcock. The producer, in some instances such as the one mentioned above, might have a situation that is fragmented. The producer, in such a situation, will have many associates with him so that they may help him with his tasks. In other instances, he may not be the sole producer of the film and instead have many producers with him, and each of them will be performing different roles for the produ ction. One of the producers will be in charge of the business activities while the other can handle creative responsibilities in the production of the film. One of the producers, on the other hand, can be a major investor and, therefore, may not be directly involved in the production of the film. A co-producer may buy the script or the film’s star to the production, on the other hand. Martin Scorsese’s film of ‘The Aviator’ had four producers – Michael Mann, Graham King, Sandy Climan, and Charles Evans Jr. - sharing the responsibilities. A producer is, therefore, responsible for providing the final film to the audience. He, therefore, enjoys the entire responsibility of the film. In several occasions, a writer, star of a film, or a director will produce his own film for having a full artistic control of the film. The most spectacular and perilous example being of Francis Ford Coppola who was the co-writer, producer and director of his most famous fi lm ‘Apocalypse now’. Producing children films have a different experience because the producer usually chooses to be attached to a specific project together with his team. Most of the children films have limited resources, and it is the responsibility of the producer to make the film possible. The producer will work together with his people, together with the director of the film and try to achieve the specific goal

Colonization of Brazil Essay Example for Free

Colonization of Brazil Essay In 1549, the Captaincy Colonies of Brazil were united into the Governorate General of Brazil, where they were provincial captaincies of Brazil; Luà ­s Teixeira, 1574. Main article: Colonial Brazil Explorer Pedro à lvares Cabral landed on April 22, 1500 in what is today Porto Seguro, Brazil. Permanent habitation did not begin until Sà £o Vicente was founded in 1532, although temporary trading posts were established earlier to collect brazilwood, used as a dye. From 1534 to 1536, 15 Captaincy colonies were created in Portuguese America. The captaincies were autonomous, and mostly private, colonies of the Portuguese Empire, each owned and run by a Captain-major. In 1549, due to their failure and limited success, the Captaincy Colonies of Brazil were united into the Governorate General of Brazil. The captaincy colonies were reorganized as provincial districts to the Governorate. The captaincies continued to be ruled by their hereditary captain-majors but they now reported to the Governor-General of Brazil. The new system was implemented so that Portuguese America could be managed correctly and provide a steady and wealthy income for the Portuguese Empire. The capital of the new governorate established its capital at Sà £o Salvador and the first Jesuits arrived the same year. With permanent settlement came the establishment of the sugar cane industry and its intensive labor demands which were met with Native and later African slaves. From 1565 through 1567, Mem de Sà ¡, the third Governor General of Brazil, successfully destroyed a ten year-old French colony called France Antarctique, at Guanabara Bay. He and his nephew, Està ¡cio de Sà ¡, then founded the city of Rio de Janeiro on March 1567. In 1621, Philip II of Portugal divided the Governorate General of Brazil into two separate and autonomous colonies, the State of Maranhà £o and the State of Brazil. Regarding this period it is preferable to refer to Portuguese America rather than Portuguese Brazil or Colonial Brazil, as the states were two separate colonies, each with their own governor general and government. Between 1630 and 1654, the Netherlands came to control part of Brazils Northeast region, with their capital in Recife. The Portuguese won a significant victory in the Second Battle of Guararapes in 1649. By 1654, the Netherlands had surrendered and returned control of all Brazilian land to the Portuguese. In 1751, the State of Maranhà £o was restructured into State of Grà £o-Parà ¡ and Maranhà £o, with a new capital and government. In 1772, the State of Grà £o-Parà ¡ and Maranhà £o was split into two new states, the State of Grà £o-Parà ¡ and Rio Negro and the State of Maranhà £o and Piauà ­. The new states would fair poorly and only last 3 years. In 1775, the three colonies of Portuguese America (the State of Brazil, the State of Maranhà £o and Piauà ­, and the State of Grà £o-Parà ¡ and Rio Negro) were united into a singular colony, under the State of Brazil. This arrangement would last until the end of Colonial Brazil. As a result, Brazil did not split into several countries, as happened to its Spanish-speaking neighbors.

The Barriers for Women in Career Advancement

The Barriers for Women in Career Advancement Chapter 2 LITERATURE REVIEW This sections presents a review of literature pertinent to this study including a history of mentoring, the barriers for women in career advancement, the relationship between mentoring and career advancement, mentoring in healthcare administration, and the advantages and disadvantages of formal and informal mentoring. History of Mentoring Mentoring is rooted in Greek mythology and arose as a concept in a story where Athena, the goddess of wisdom, assumed a male form and called herself Mentor. Athena acted as a surrogate parent to Telemachus when the boys father, Odysseus, fought in the Trojan War. Athena provided guidance and instruction to the boy as the latter assumed the leadership of the household and groomed him to be Ithacas future ruler (Butler, 1944). Hence, the concept of mentoring has been shaped by the notion of a relationship where a more experienced adult guides a youthful individual (Kram, 1985). More specifically, Kram (1985) describes mentoring as â€Å"a relationship between a younger adult and an older, more experienced adult [who] helps the younger individual learn to navigate the adult world and the world of work† (p. 2). Lacey (2001) states that the term â€Å"mentor† has since evolved to represent either a counselor, teacher, or friend and the mentoring relationship now connotes a p artnership where the primary purpose is the exchange of information and knowledge distinct to a given industry or organization. Other authors refer to mentoring relationships as â€Å"sponsor, patron, and godfather† relationships (Rowe, 1978, as cited in Kram, 1985). A literature review on mentoring across various disciplines by Hayes (2001) produced the definition of mentoring â€Å"as a process of building trust between two people, one is experienced and the other is a newcomer† (p. 29). Carmin (1988) provides a comprehensive definition of mentoring: Mentoring is a complex, interactive process, occurring between individuals of differing levels of experience and expertise that incorporates interpersonal or psychosocial development, career, and/or educational development, and socialization functions into the relationship. This one-to-one relationship is itself developmental and proceeds through a series of stages which help to determine both the conditions affecting the outcomes of the process. (p. 10) Mentoring as a field of study started with the 1978 research of Levinson et al. on adult mens career development experiences (as cited in Kram, 1985). Levinson and his colleagues concluded that the mentoring relationship was a pivotal experience in a young adults life because aside from receiving knowledge from mentors, the experience also shapes a persons self-esteem and professional identity. Kram (1995) identifies two broad types of mentor functions: career-related support and psychosocial support. Career-related support refers to the support mechanisms provided by the mentor that boosts the mentees career advancement within the organization. Component functions associated with career-related mentoring include â€Å"sponsorship, exposure and visibility, coaching, protection, and challenging assignments† (p. 86). Due to the mentors influence and high status, experience, and leadership position in the organization, the mentee receives the best hands-on training and gets assistance on learning more about the organization itself and its inner workings, receives exposure to the mentors social networks, and acquires promotions. In this regard, the mentor sees him or herself in the mentees shoes and want to groom a future executive in his or her fashion. Allen Eby (2002) view that mentors and mentee alike benefit from the mentoring relationship and that mentors are fuel ed by the desire to ensure the success of the next generation of leaders. Kram (1985) theorized the mentors can provide five specific career development functions (as cited in Ragins Cotton, 1999): Sponsoring promotions and lateral moves (sponsorship); Coaching the protà ©gà © (coaching); Protecting the protà ©gà © from adverse forces (protection); Providing challenging assignments (challenging assignments); and Increasing the protà ©gà ©s exposure and visibility (exposure). (p. 530) The second mentoring function is psychosocial in nature. The psychosocial function of mentoring addresses â€Å"those aspects of a relationship that enhance an individuals sense of competence, identity, and effectiveness in a professional role† (Kram, 1985, p. 32). Krams mentor role theory (1985) suggests that there are four components of psychosocial support that mentors can provide to mentees (as cited in Ragins Cotton, 1999): Helping the protà ©gà © develop a sense of professional self (acceptance and confirmation); Providing problem-solving and a sounding board (counseling); Giving respect and support (friendship); and Providing identification and role modeling. (p. 530) Where career support is dependent upon the mentors power and influence within the organization, psychosocial support focus on the emotional bond and the interpersonal relationship underlying the mentoring relationship. Career support aims at advancing the protà ©gà ©s career while psychosocial support is geared at improving the protà ©gà ©s personal development. Barriers for Women in Career Advancement Compared to several decades past, women have made leaps in terms of advancing toward senior executive positions formerly monopolized by men. However, career advancement opportunities for women still lag considerably compared to the men. Tharenou (1999) estimates that although women in developing countries make up almost half of the entire workforce, only 5 percent of them are situated in top executive positions. A worrisome fact is that while there seems to be equal opportunities for men and women in entry-level positions, the road toward the more senior levels are unfortunately blocked for women. While is undeniable that the greater workforce composition of women is one of the most positive social changes in the twenty-first century, struggle for equal opportunity persist as women are still excluded from the top positions in the organizational hierarchy. This phenomenon has been referred to as the â€Å"glass ceiling,† a term originally used in 1986 by a Wall Street journalist to connote the status of women in the corporate world. The term was coined as a description of the complex barriers that block womens opportunities to break through the top levels in the organization. This â€Å"glass ceiling† is especially evident when one looks at rarity of female senior executives in organizations of virtually all disciplines. The concept of the glass ceiling was recognized and accepted as a public term when the 1992 Federal Glass Ceiling Commission concluded that there were indeed several barriers that hindered women and other minority groups to achieve their full potential within the career ladder. The same study confirmed that â€Å"gendered† structural and organizational barriers prevented women from attaining the most senior level positions in several companies. Moreover, it lamented on the so-called â€Å"hegemonic masculinity† that is pervasive in the organizational culture in corporate America (Woody Weiss, 1994). Many studies have reported on the various barriers that women encounter during professional advancement. A report by womens group Catalyst (1994) listed the most common barriers identified by mid-level managers that prevent them from advancing further into the top-level positions. These barriers include (as cited in Arnold Shinew, 1997): stereotyping and preconcepts about suitability for leadership positions; exclusion from informal networks of communication; absence of effective management training for female employees; failure to hold upper level managers accountable for developing and advancing women; inadequate appraisal and compensation systems, leading to inequities in salaries; inflexibility in defining work schedules; and absence of programs that enable employees to balance work/non-work responsibilities. (pp. 42-43) The work of researchers Henderson and Bialeschki (1995) has been influential in comprehensive studies that aim to identify the different barriers that women face in their pursuit of upward career mobility. They conducted a nationwide survey among women practitioners in the recreation and leisure industry. The researchers grouped the different barriers into three broad categories: individual, organizational, and home/family. By examining career patterns, family situations, career satisfaction, and equity in the workplace issues, they found that stereotyping and gender-based discrimination remains the greatest barrier for women that prevent them from advancing to the top tier of the corporate ladder. More than half of them also reported being sexually harassed. Other identified barriers include the lack of training, lack of mentors, and womens exclusion from â€Å"male-only† networks. Another study by Frisby and Brown (1991) surveyed 30 women mid-level managers belonging to leisure-oriented organizations in order to examine their career experiences as they struggled their way to the top. Consistent with previous findings, women in middle management reported that the most common barriers they encountered from advancing in their careers include career interruptions due to pregnancy or family issues, the lack of role models or mentors, the lack of support from senior executive to promote women, exclusion, gender stereotyping, personal factors, and exclusion from male-dominated social networks. Frisby (1992) did a follow-up study to examine in a more comprehensive manner the factors that hinder the career development of women in leisure organizations. Using a descriptive-quantitative design, Frisby grouped the various barriers reported by women managers that have influenced their career direction and mobility. There were legislative factors such as gender discrimination, pay equity, and laws on sexual harassment; organizational factors such as patriarchy, exclusion from networks, flexible work options, difficulty in dealing with male-dominated organizational culture, lack of training and mentoring opportunity; and individual factors such as gender, education, and geographical mobility; and lastly, family factors that include lack of support from spouse and difficulty balancing work-family responsibilities. Due to the complex and varied nature of identified barriers for women, studies by Henderson Bialeschki (1995) and by Woody Weiss (1994) have grouped these barriers into three categories: a) Individual factors; b) Organizational/Structural factors; and c) Family or Home-related factors. Individual factors as barriers Individual traits and skills are often attributed for laggard career advancement among females. Individual factors such as age, educational attainment, skills, experience, proficiency, or ability are related to advancement. There remains gender stereotypes on what men can do that women cannot that justifies greater upward mobility for males. Some express that women lack the necessary attributes such as assertiveness, motivation, or networking skills to advance in careers (Vecchio 2002). The simple fact of â€Å"being female† thus becomes a potent barrier for career advancement among women. For instance, there is a double standard when it comes to appreciating leadership in females. Morrison, Greene and Tischler (1985) opine that when women display competence in leadership, they are viewed negatively while men who visibly lead are appreciated. Similarly, succession in vacated executive positions is usually based on the gender of the previous occupant of the position or the job. Since most senior executive positions are dominated by males, women are immediately excluded from consideration. Moreover, females are placed in â€Å"traditionally-female† positions such as staffing and human resources and cannot be promoted to higher positions that are â€Å"traditionally-male† in nature. Age can also be a barrier as individuals who are deemed â€Å"too young† or â€Å"too old† may not be deemed suitable for senior executive positions. Organizational factors as barriers Most research studies conclude that the biggest barriers to career advancement among women are beyond their personal control. The Glass Ceiling Commission indicts organizational and structural barriers as the most predominant barrier toward womens upward climb in the career ladder (Woody Weiss, 1994). Bergmann (1986) opined that organizational structures specifically job assignments are designed to prevent women from ascending to the top. Job assignments are considered to be the primary route for career advancement. Organizational structures â€Å"steer away† womens potential for upward mobility by confining them to work roles that are considered to be â€Å"womens occupations.† Bergmann cites a study by Forbes that the quickest way to the top of corporations is placement in functional areas or crucial job assignments that lead to the accomplishment of critical organizational tasks (p. 88). Klenke (1996) suggests that women face an exclusion policy that prevents them from penetrating the â€Å"old boys† network. Access to such networks is considered a significant step to gaining upward mobility in organizations. One can access information and learn more about the organization not possible in regular communication channels. Another barrier cited by women is the lack of mentoring opportunities from male superiors. For instance, Dreher and Cox (1996) found that females find it difficult to gain informal mentors who are male. If they do find a male mentor, they also face challenges in the course of the mentoring relationships especially in relation to its nature and possibility of misinterpretation. Some female managers even report being subjected to sexual harassment. Cooper Jackson (2001) contends that the scarcity of women role models is another perceived barrier toward advancement. Organizational leadership is predominantly patterned after the male form of leadership. Since acquiring senior executive positions are blocked, developing women role models that would inspire and motivate women and neutralize male-dominate culture in the organization becomes challenging. Moreover, because women lack opportunities for role modeling or mentoring relationships, they often fail to plan their career and build effective networking strategies. The reality of stereotyping has been found to affect womens career advancement deeply. Because of gender stereotyping, women feel isolated and discouraged because they perceive themselves unable to blend well or fit in with the patriarchal culture of senior executive leadership. Sometimes, this perception leads them to believe that have to change considerably in order to suit the male-dominated culture of the top hierarchy. Davidson and Cooper (1986) report that gender stereotyping in the organization leads to higher stress levels among women than men. This is because gender stereotyping often pressures women to exert extra effort or to work harder and perform better than their male counterparts in order to prove themselves equal to them. Women tend to believe that in order to achieve their career goals, they have to over-perform to counter the effects of negative gender stereotyping. Even when women are promoted and do acquire senior executive status, there is a prevailing norm that they have to perform even better than their male colleagues to prove themselves worthy of the position. Powell and Butterfield (as cited in Collinson Hean, 2001) state that stereotyping also leads to social isolation among female managers and their heavy dependence on formalized relationships for career advancement. Female managers put a prime on their professional portfolio and credentials when they pursue promotional opportunities whereas men can depend on informal networks to advance in their careers. Collinson and Hearn (2001) believe that unless the patriarchal nature of institutions are broken down, women will find it difficult to advance their careers in what is considered male territory. They define patriarchy as a process and a context through which male supremacy is promoted by men and institutions. Patriarchy is a stumbling block for women because it â€Å"control[s] access to hierarchical power and characteristics of knowledge claims† (Collinson and Hearn, 2001, p. 23). In this environment, cultural practices and information flow signify male authority, hence, placing women as mere subordinates to men. However, the problem with patriarchy is that it is a â€Å"complementary process† that is legitimized by both women and men and forms part of the organizational culture. In this manner, male dominance becomes a self-perpetuating phenomenon in organizations. Moreover, Collison and Hearn (2001) opine that executive culture is a male realm. They believe that wome n are not accepted wholly into the workforce but are merely tolerated. Hence, the notion of â€Å"patriarchal elitism† especially in top executive culture is widespread (p. 8). Pringle (1999) contends that female managers lack access to networks, trainings, and mentoring programs because they are usually gender-based and male-gendered. The domination of men in organizations is sustained with constant identification with one another. Perpetuating a gendered organizational culture leaves women managers isolated and places them in a situation where executive leadership feels very much like engaging in constant â€Å"physical combat† (Sinclair, as cited in Pringle, 1999, p.8). Home-related factors as barriers The barriers that women encounter extend far beyond the confines of the workplace to the home. For many female managers, the home environment presents several obstacles that must be overcome in order to achieve upward mobility. One obstacle is that some women managers, especially, those with families, experience the so-called â€Å"second shift syndrome† where they must work on the first shift in the workplace and continue on the second shift in the home environment. The burden of juggling work-related goals with family responsibilities is a serious concern for some women. Women who find themselves in this circumstance are also called â€Å"dual career women† where performance at work and at home are necessary. To perform this balancing act between professional development and personal life may prove too difficult for some women in many ways. Some of them eventually may find inadequate support from their respective families to pursue career advancement goals. A 1995 survey by recruiting company Robert Haff and Associates (1995) found that more than 80 percent of women managers who were interviewed preferred a job that featured more flexible hours, provided more family time, and slow-paced advancement than grueling jobs that featured rapid career mobility. In a sense, because of additional responsibility at home and with their families, women do not perceive career mobility as â€Å"a methodical rise to power† (Aburdene Naisbitt, as cited in Pringle, 1999, p. 43). Unlike the men, women do not focus on the singular objective of professional advancement but struggle to â€Å"do it all† and come up with more creative ways to reap professional success. Research also reports that women managers continue to bear the brunt of carrying the â€Å"double burden† of family and work. They have to be successful equally in the home and at work. In the home environment, they need to assume the manifold tasks of wife and homemaker and struggle to become equals with men in the workplace at the same time. Sue Newell opines that so long as women continue to juggle these dual roles, they may never achieve the parity they need and deserve in relation to men in the work environment (Newell, 1992). However, studies have also found the home and family-related barriers do not necessarily interfere with motivation and career success among many women. The problem with having the additional burden of family responsibility for women is that it is viewed as a negative thing. Research has suggested that many companies look at women with home-related commitments with disfavor (Swiss Walker, as cited in Pringle, 1999). What is worse is that some women may even be penalized career-wise for having commitments outside of the professional realm. Having marital and family responsibilities may not interfere in terms of commitment among women but these factors might slow down the promotional opportunities of woman managers. Some women have reported that the workplace was inviting and conducive to success when they were single and changed considerably to a more unwelcome environment when they got married and had children. In an article, management expert Douglas T. Hall (1990) suggested that in order to provide more access for women in terms of career advancement, companies need to come up with strategies that promote balance between work and family responsibilities. Among the strategies he recommend were more flexible work schedules and expanded use of home-based work option.

Processes of Drugs Metabolism in the Body

Processes of Drugs Metabolism in the Body Abstract Metabolism of drugs is a complex and major process within the body, occurring primarily in the liver. The aim of metabolism is to make the drug more polar to enable excretion via the kidneys. The basic understanding of drug metabolism is paramount to ensure drug optimisation, maximum therapeutic benefits and a reduction in adverse effects. Essentially drug metabolism is broken down into two phases, Phase I and Phase II. Phase I is concerned with the biotransformation of compounds, and then transferred to Phase II. However, for some drugs this is the end of their metabolic journey in the body, as they produce more polar compounds which are readily excreted. Phase II reactions are where compounds are conjugated to produce more water soluble compounds for easy excretion. Phase I reactions are dominated by the Cytochrome-450 enzyme superfamily. These enzymes are found predominantly in the liver, which is the major site of drug metabolism. However, drug metabolism is not localised merely to the liver, there are other major sites at which this process occurs. Some of these sites include the skin, lungs, gastro-intestinal tract and the kidneys; close to all tissues have the ability to metabolise drugs due to the presence of metabolising enzymes. The most important enzymes are the cytomchrome-450 superfamily, which are abundant in most tissues. Inactive drugs with the ability to reconvert to the active parent drug once metabolised to exert their therapeutic actions are defined as prodrugs. They are classified depending on the site of conversion and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within the body, compared to their active metabolites. Individual drug metabolism may be affected by variant factors, such as, age or sex. Drug metabolism can cause an increase in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this toxicity can occur in Phase I metabolism e.g. acetaminophen. However, in some circumstances toxicity occurs in Phase II e.g. zomepirac, polymorphism can also cause idiosyncracity of certain drugs to be toxic. 1.1 Phase I Phase one, otherwise known as drug biotransformation pathway is generally broken into oxidation, reduction and hydrolysis. A reaction under this phase involves an addition of oxygen molecule aiming to improve the water solubility of drugs. As the result some metabolites from this phase can be extracted immediately if they are polar enough however at times a single addition of oxygen is not sufficient enough to overcome the lipophilicity of certain drugs and hence their metabolite from this phase has to be carried onto phase II for further reactions. Major example of Oxidation: Accounting for roughly 20 complex reactions the most important oxidative metabolic pathway dominating phase I is the cytochrome-P450 (CYP450) monooxygenase system processed by C-P450. Located primarily in the liver CYP450 was found to be present in all forms of organisms, including humans, plant and bacteria. It is important to note that the function of CYP450 goes beyond drug metabolism but it is also involved in metabolism of xenobiotics, fat soluble vitamin and synthesis of steroids. With substrate specificity of more than 1000 and its ability to produce activated metabolites such as epoxide are the underlying reason for its dominance and importance in drug discovery. The general mechanism the CYP450 monooxygenase oxidation is: R + O2 + NADPH + H+ à   ROH + H2O + NADP+ (fig 2) From the above formula it can be this reaction is of NADPH (Nicotinamide adenine dinucleotide phosphate) and an oxygen molecule dependent. As mentioned above oxygen is important to increase the water solubility and in the same manner NADPH is also important for oxygen activation and source of electron. Also important for activation of oxygen is the presence of cystine amino acid located near the protein terminal carboxyl of CYP450. Among the 500 amino acid present in CYP450, cystine has proven to be most important as it activates the oxygen to a greater extend. This is due to the fact that it contains a thiol group as one of its ligand and it is the thiol which alerts the reactivity. Highlighting the numerous intermediate structures involved as well as function of iron, oxygen and proton (Figure) shows the catalytic conversion required for cp450 oxidation reaction to place. The binding of the substrate with low spin ferric CYP450 enzyme induces a change in its active site. This will effects the stability of the water ligand and will displace it (shown in the diagram from a-b). Containing a high spin heme iron the enzyme and substrate form a ferric complex. The change in electronic state will result in the release and transfer of one electron from NADPH via electron transfer chain (reducing ferric heme iron to ferrous state) and thus reduction of the complex. The second electron is transferred when the complex reacts covalently with the oxygen forming a new ternanry complex. Initially the complex is an unstable oxy-P450(diagram d), however this is reduced to produce ferrous peroxide by a loss of an electron. This intermediate is short lived and undergoes protonati on twice resulting in a release one water molecule. Out of the oxygen molecules released one in incorporated in this water molecule and the remaining into the substrate. Another method of forming the iron-oxo intermediate is via the peroxide shunt which elimited steps from C to F. Some of the common addition of oxygen molecule reactions which CYP450 dependent are known as epoxidation (of double bond), N-hydroxylation, oxygen/nitrogen/ sulfur dealkylation, s-oxidation, dechlorination, oxidative desulfurisation and aromatic hydroxylation. Note they all follow the same principle of adding oxygen molecule to the substrate. The diagram below provides an example of how these reactions are processed: Aromatic hydroxylation substrate mostly produces phenols such as that seen on figure 3. The production of Phenol can be either via a non enzymatic rearrangement or by Epoxide hydrolase and cytosolic dehydrogenase which will ultimately give rise a catechol. The position of hydroxylation depends greatly on the nature of the R- group attached to the ring; an electron withdrawing group will position the -OH group on the metha while the electron donating will position it on the para or ortha. Aromatic hydroxylation also involves a change in NIH shift, which involves the movement and shifting of the R group to an adjacent position during the oxidation. It is important to note that certain substrate for aromatic hydroxylation can also be oxidized via the aliphatic (C-H) hydroxylation. Under such condition the aliphatic C-H) hydroxylation will oxidize it. Aliphatic dehydrogenation can also occur involving electron transfer to the CYP450. Currently more than 50 CYP-450 has been identified in human, however the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand side clearly demonstrate just how much of drug metabolism is CYP450 3A responsibility in comparison to other, accounting for roughly 50%. Metabolism of drugs given orally are greatly determined by CYP450-3A primarily because this enzyme is present in both the liver and intestine and thus providing a barrier for all drugs before they can enter the systemic circulations, otherwise commonly known as ‘first pass effect. Upon entering the drugs are taken up via passive diffusion and/or facilitated diffusion or active transport into the entercocyte where they can be metabolized by CYP450-3A. They can once again be metabolized by the very same enzyme when they enter the liver (hepatocyte) ,which unlike the intestine in order to reach the systemic circulation it is unavoidable. Th is family of enzymes are also known to be cause of many serious adverse effects as they are influenced by diet and drug components, hence drug-drug and drug-food interactions is an important factor. Flavin monooxygenases Similar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major role in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also oxygen and NAPDH dependent, Flavin monooxygenases has much broader substrate specificity than CYP450. Once they have become associated with substrate the flavin monooxygenases is activated into 4ÃŽ ±-hyroperoxyflavin and unlike CYP450 the oxygen activation takes place without the need for substrate to bind to the intermediate. This pre-activated oxygen means that any compound binding to the intermediate is a substrate to be metabolized. The fact that this enzyme is able to remain stable and lacks any need for correct arrangement and disorientation of the substrate gives it ability to withhold all the energy required for the reaction to takes place and hence as soon as appropriate lipophilic substrate becomes available it starts the process immediately. Adverse side effects are rarely associated w ith these enzymes. The binding of oxygen to the reduced flavin is processed via a non-radical nucleophilic displacement. The substrate is oxidized via a nucleophilic attack by the oxygen that is located at end of 4ÃŽ ±-hyroperoxyflavin. This is then followed by cleavage of peroxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4ÃŽ ±-hyroperoxyflavin has been regained using NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times undergo reduction back to its original parent form. Alcohol dehydrogenase and aldehyde dehydrogenase These families of enzymes are both zinc containing NAD specific and catalyze the reversible oxidation of alcohol and aldehydes respectively. Grouped into 1-6 Alcohol dehydrogenase, are homodimer that exist in the soluble section of the tissue. It is involved in metabolism of some drugs such as cetirizine however it is more predominantly known as alcohol metabolism enzyme specifically ethanol, whether products of peroxides or that of exogenous (i.e administered drugs). It is important to note that although alcohol dehyrogenase is the main metabolic pathway for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulting in adverse side effects between alcohol and with certain analgesics drugs. Alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a longer half life and rapid absorption from the gut, methanol can result in series of unpleasant side effects and metabolic acidosis, hence highlighting the importance of alcohol dehydr ogenase. Similarly, aldehyde dehydrogenase catalysis the oxidation of aldehyde to its corresponding carboxylic acid. Class one of alcohol dehydrogenase plays a major role in detoxification of anti cancer drugs. Alcohol dehydrogenase is also involved in reduction pathway of aldehyde or ketone back to its pharmacologically active alcohol form. Monoamine oxidase and diamine Located in liver, intestine and kidney as few of its site, this membrane bound enzyme is divided into two classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deamination to aldehyde, these enzymes are flavin containing enzymes and within their cysteinyl residue the flavin is linked to the covalently bounded flavin via a thioether. Monoamine oxidase has several substrates, ranging from secondary to tertiary amines that have alky group smaller than methyl. The general mechanism for this enzyme is the two electron oxidation shown below: R.CH2.NH2 + O2 + H2O à   R.CHO + NH3 + H2O2 (fig 7) As it can be seen this reaction requires oxygen to react and a hydrogen peroxide is produced as for every â€Å"one molecule of oxygen is absorbed for every molecule of substrate oxidized† (Principle of drug metabolism, 2007). Proportional to the rate of oxygen uptake this is commonly used to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenous substrates such as noradrenalin while monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their common substrate is dopamine. Inhibition of monoamine oxidase has long been of an interest for scientist in treatment of several of illness such as depression. Present in liver, lungs and kidney as few of its locations diamine oxidase also catalyses the formation of aldehyde from histamine and diamines in the same manner. Reduction This pathway of metabolism is enzymatically the least studied in phase I and yet it plays an important role in metabolism of disulfides and double bonds of for example progestational steroids as well as dehydroxylation of aliphatic and aromatic compounds. In general ketone containing xenobiotics are more readily metabolized and eliminated via this pathway in the mammalian tissue. This is due to the fact that the carbonyl group is very lipophilic, thus the lipophilicity will be reduced and elimination is ensured as ketone is converted to alcohol. One of the major enzymes involved in this pathway is the NADPH cytochrome P450 reductase. Containing flavin adenine dinucleotide and flavin mononucleotide is an electron donor playing an important role in the metabolism of drugs such as chloramphenicol by reducing its nitro group. Hydrolysis As the name suggests this pathway uses water to cause a breakage of a bond. Major enzymes under this pathway are the amide and ester hydrolysis and hence amide and esters are the common substrates. Naturally esters are much easier targets to esterase hydrolysis than amides. A very common amide substrate is a local anesthetic, Lidocaine and an antiepileptic drug known as levetiracetam. Catalyzing ester and certain type of amides are the group of enzymes referred to as carboxylesterase. This enzyme hydrolysis choline like ester substrate and procaine. As a rule, the more lipophilic the amide the better it be accepted as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and slower to be hydrolysed and will usually be eliminated unchanged at a high percentage such as that for atropine, eliminated 50% unchanged. A very good example of esterase enzyme is the paraoxonase. The hydrolysis of substrate such as phenyl acetate and other acyl esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are imperative for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the carbon attached to the oxygen resulting in a formation of tetrahedral orientation. The presence of a hydrogen donor to the improvers the leaving group abilities is the final requirement. 1.2 Phase II (Second part of drug metabolism): Second part of drug metabolism, involves introduinh of new ionic chemicals on to the substrate (including the metabolites from phase I) in order to increase its water solubilyt for elimination. This phase is usually refered to as conjugation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major conjugation of phase II. Methylation is the transfer of methyl group to the substrate from cofactor s-adenosyl-L-methionine (fig 9). S-adenosyl-L-methione is an active intermediate that receives a transferred methyl group from methionine after its linkage with ATP in presence of adenosine transferase enzyme. It is this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group becomes attached to the sulfonium center marking â€Å"electrophilic character† (Principle of drug metabolism, 2007). Depending on the functional group present on the substrate Conjugation via methylation is broken down to nitrogen, oxygen and sulfate methylation. O-methylation O-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to ‘Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to size of the substituted group, the larger it is the slower the rate of reaction degree of acidity of the catechol group itself. N-methylation Naturally this reaction has substrate specificity of amine, involving however primary and seconday only. Unlike the above reaction, N-methylation consists of several enzymes, all of which are categorized in accordance to the specific type of amine substrate which they catalyze. Enzymes such as amine-N-Methyltransferase, nicotinamide-N-methyltransferase and histamine-N-methyltransferase are few examples. Despite the substrate specificity all the enzymes involved do however follow the same principle of transferring methyl fromcofactor s-adenosyl-L-methionine to the substrate. With drug substrates such as captoril, reactions of N-methylation can be broken down into two distinct types as illustrated in Fig 11. Reactions that have a low pharmacological significant yield an ineffective n-methylation as the substrate and the product have a same electrical state thus the metabolites are usually less hydrophilic than parent. As it can be seen from fig 7a, in these reactions one proton is exchange for a methyl group. On the other hand a more hydrophilic product and an effective reaction of detoxification is achieved with pyridine type (nitrogen atom) substrate. These substrate will result in a creation of positive change on the product (fig 7b) rather than an exchange process. Sulfate and phosphate conjugation Sulphate conjugation is one of the most important reactions in biotransformation of steroids, effecting its biological activates and decreasing its ability for its receptor. Nucleophilic hydroxyl groups such as alcohol and phenol, primary or seconday amine and drug containing a SO-3 group are the common substrates for this pathway. Generally sulphate are transferred via a membrane bound enzyme named sulfotransferase (located in golgi apparatus) from their cyclic cofactor 3-phosphoadenosine 5 (shown in fig 8 ) to substrate. 3-phosphoadenosine 5 is formed in a reaction between adenosine triphosphate and inorganic sulfate where the sulfate/phosphate group are bonded via a anhydride linkage which gives rise an exothermic reaction when broken, hence providing the energy for the reaction. In human there is two class, SULT 1A- 1E and SULT 2A-2B, each of which will have different specificity yet with overlaps. This enzyme acts on both endogenous as well as exogenous compounds as long as they possess an alcohol (less affinity with varying product stabilities) or phenol (products are stable arly sulfate esters with a high affinity). Substrates are generally of medium sized, highly ionized and hydrophilic, hence excreted easier via urine. The rate of this pathway is determined by the lipophilicity and nature of amino acid present on the substrate. Interestingly phenol is also of an interest for the Glucoronic conjugation pathway and are metabolized by this when they are at high concentration and 3-phosphoadenosine 5 becomes rate limiting. The sulfate conjugation will produce ester sulfate or sulfamide some of which will undergo further heterolytic reaction leading to electrophilic substrate and hence toxicity. Unlike the sulfate conjugation the phosphate conjugation is less common unless the drug in question is anticancer or antiviral. Catalyzed phosphotransferases. conjugation The most important and major occurring metabolic pathway of phase II is the glucoronic conjugation, accounting for the largest share of conjugated metabolite in the urine. This pathway is important due to the fact there is a high availability of glucucronic acid, huge substrate specificity and the wide range of poorly reabsorbed metabolite. The glucoronic conjugation takes place as the glucoronic acid is transferred to the acceptor molecule from its cofactor uridine-5-diphosphh-alpha-glucoronic acid (fig 9 ) of which glucoroniuc acid is attached in 1 ÃŽ ± configuration. However products produced are in ÃŽ ²-configuartion. This is due to the nucleophilicity of the functional groups of the substrate. To be able to undergo this pathway of metabolism the functional group of drugs in question must have nucleophilic characteristics. Generally the drug that are at high affinity for this pathway is firstly phenol (paracetamol) and then alcohol (primary, secondary or tertiary) suc h a morphine. The transformation of the drugs involves a condensation reaction and hence release of water, while the conjugate replaces the hydrogen on the -OH group. Present in the ER uridine-5-diphosphae-alpha-D glucoronic acid is produced due to oxidation of carbon position six of UDP-ÃŽ ±-D-glucose. Interaction of this co factor with the substrates is catalysed by one the two classes of UGT1 or UGT 2, present mostly in liver however still found in brain and lungs. As this pathway produces a wide variety of procucts, work has been done to divide them into four groups of O/S/C/N glucoronides, with the o-glucoronides being the most important forming a reactive metabolite known as acyl-glucuronides. Generally drugs containing functional groups such as carboxylic acid, alcohol and phenol give rise more examples shown in fig 10. Acetylation Involving a transferring of an active acetyl linked via a thioester bridge to acetyl-coenzyme A (fig below) to a nucleophilic function group of substrate this metabolic pathway mainly occurs in liver involving amino groups of medium basic properties. One of the common drug metabolized by this pathway is the para-aminosalicly. Large group of enzymes known as acetyltransferase are enzymes involved in catalyzing this pathway, among these are the aromatic-hydroxylamine O-acetyltransferase and the arylamine N-acetyltransferase. Interestingly, genetic polymerization of acetylation function has meant that the rate of reaction and occurrence of toxicity will differ in accordance to the polymers. Fast acetylation will have result in a fast conversion and elimination while slow acetylators will have the opposite effect and will lead to build of unconjugated compounds in the blood and hence leading to toxicity. Conjugation with co-enzyme A Commonly using this pathway are the carboxylic containing which are activated into an Intermediate and eventually forming a acetyl-CoA conjugate It is important to note that primary metabolites from this reaction do not show up in vivo and only in vitro, however some of its secondary and stable metabolites that have undergone further reactions do. A factor that seems to cause problems with this pathway is the occurrence of toxicity, rare but serious as it the conjugates interfere with normal endogenous pathway. A common example was seen with NSAID which have now been long removed from market. Conjugation with amino acid This metabolic pathway is the most important for carboxcylic drugs where they form conjugate with the most common amino acid, glycine. Products are non-toxic (with no exception) and more water soluble than their parent compound. The drugs first become activated to the co- enzyme A before forming an amide or peptide bond between its carboxylic group and amino acid. The enzymes that facilitate this reaction are those of N-acyl transferases, such as glutamine N-acyltransferase. Carboxylic substrate for this pathway are also of an competition for the glucoronic conjugation, at high concentration if drugs glucoronic conjugation is preferred due to high availability, while at low concentration conjugation with amino acid is used for the metabolism. Conjugations with Glutathione Conjugation with glutathione has a wide variety of substrate specificity; this is partly due to the fact that in vivo glutathione exists as in equilibrium between its oxidised and reduced form hence enabling it to accept a wider range of substrate. The reduced form of glutathione is able to act as a protecting agent as it removes free radicals while the oxidised form oxidizes peroxides. A thiol, the glutathione contains a tripeptide and with a pka of 9.0, allowing it to be an excellent nucleophile agents, due to the increase in the ionization due to the thiol group. As the result of these electrophilic groups are easily attacked, usually on the most electrophilic carbon (commonly sp3 or sp2 hybridised) that contains the functional group. Enzymes responsible for catalyzing these reactions are known as glutathione transferase, seven of which are found in human. They also serve an important role apart from catalysing as upon binding of the active side with the glutathione will results i n a decrease in pka value and hence an increase in acidity (the thiol is deprotonated thiolate), thus enhancing the nucleophilic abilities. Depending on the substrate in question the conjugation with glutathione can be divided into forms, nucleophilic substation or nucleophilic addition. During the nucleophilic addition, an addition followed by an elimination reaction occurs. Attack occur at the activate electron lacking CH2 group, which the glutathione substitutes as it becomes added on to the carbonyl as shown in fig 12. Nucleophilic substitution reaction is much more common with xenobiotic than drugs although it is seen with chloramphenicol, where its -CHCL2 becomes electrophilic due to a electron withdrawing group. One of the most important conjugation in relation to glutathione is with epoxides giving rise to a protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via dehydration catalyzed by acid giving rise to a GSH aromatic conjugate. As a final metabolite a mercapturic acid (a condensation reaction exerted by urine) as shown in (fig below) is formed via a series reactions including cleavage and n-acetylation . 2.1 Metabolism in the liver When a drug can be cleaved by enzymes or biochemically transformed, this is referred to as drug metabolism. The main site of drug metabolism within the body occurs in the liver, however, this is not the only site in which metabolism of drugs occurs, this will be discussed later. The liver ensures drugs are subjected to attack by various metabolic enzymes; the main purpose of these enzymes is to convert a non-polar drug into more polar molecules, thereby increasing elimination via the kidneys. The polar molecules formed are known as metabolites, these lose a certain degree of activity compared to the original drug. Metabolic enzymes, cytochrome P450 enzymes enable the addition of a polar compound to particular drugs, making them now polar and more water-soluble. On the other hand, some drugs may become activated and then have the desired effect within the body, these are referred to as pro-drugs; and will be considered in greater detail later. Drug metabolism is split into two stages known as Phase I reaction and Phase II reaction, both of which have been discussed earlier. Certain oral drugs undergo a first pass effect in the liver, thereby reducing bioavailablity of the drug. This can lead to numerous problems, such as, individual variation that can then lead to unpredictable drug action, and a marked increase in metabolism of the drug. These problems related to the first pass effect may hinder the desired therapeutic effects from being fully achieved. Many drugs undergo first pass metabolism, previously seen as a disadvantage, but now due to a greater understanding of hepatic metabolism it can be used advantageously, for example Naproxcinod. Naproxcinod is related to naproxen, which will be discussed below, we will also be examining the metabolism of propanolol. Naproxcinod is derived from the non-steroidal anti-inflammatory drug (NSAID), Naproxen. First we will examine the metabolism of Naproxen (6-methoxy-a-methyl-2-naphthyl acetic acid). Naproxen is a widely used NSAID, possible of blocking both cyclo-oxygenase isoforms 1 and 2, therefore making it a non-selective inhibitor of these isoforms. Rheumatoid arthritis and osteoarthritis are the main reason for use of naproxen, which is administered orally as the S-enantiomer. This particular drug is well absorbed by the body and is metabolised in vivo to form various metabolites, the major metabolites being naproxen-b-1-O-acylglucuronide (naproxen-AGLU) and desmethyl-naproxen (DM-naproxen). Naproxen is conjugated in a Phase II reaction with glucuronic acid to form an acyl glucuronide (Diagram 2), with the intermediate being DM-naproxen. Usually conjugation reactions produce inactive metabolites, however with glucuronic acid the metabolite formed can occasionally become active. This reaction is facilitated by the superfamily UDP-glucuronosyl transferase (UGT) enzymes. The major UGT isoforms found in the liver are: 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7 2B10, 2B15, 2B17 and 2B28. The isoform 2A1 is found mainly in the nasal epithelium, while 1A7, 1A8 and 1A10 are only localised to the gastro-intestinal tract. UGT acts as a catalyst enabling glucuronic acid to bind to naproxen at the carboxylic acid group via covalent bonding. It has been found that all UGT isoforms contribute to the conversion of naproxen to its metabolite naproxen-AGLU, except UGT-1A4, 2B4, 2B15, and 2B171. This reaction produces a highly polar glucuronic acid molecule bound to naproxen. Its main mode of elimination is through the urine. The next major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An unstable metabolite is formed during this process, however it is hydrolysed immediately to DM-naproxen. The enzymes involved in this reaction are cytochrome P450 1A2 and 2C9 from Phase I. Once DM-naproxen has formed it is glucuronidated with the help of UGT enzymes 1A1, 1A3, 1A6, 1A9 and 2B7 and converted to its acyl glucuronide. UGT-2B7 is a high affinity enzyme and so has a high activity in this process, as does UGT-1A6. UGT-1A4, 2B15 and 2B17 do not contribute to the acyl glucuronidation process1. DM-naproxen is also converted to phenolic glucuronide; this is formed by the UGT enzymes 1A1 and 1A9. Enzymes UGT 1A3, 1A6 and 2B7 appear to play no part in this reaction. UGT 2B7 works well in glucuronidating the carboxylic acid moiety in particular drugs; however it is unable to glucuronidate the phenolic group, so for this reason is not involved in forming phenolic glucuronide. The aim of hepatic metabolism is to ensure metabolites are made more water-soluble hence easily excreted. All metabolites formed from naproxen are water soluble and easily eliminated from the body. However, there are two metabolites that have been found to be far more water soluble, these are naproxen-AGLU and acyl glucuronide2. Huq (2006) explains this is due to the high solvation energy of both metabolites compared to naproxen and its other metabolites. Metabolites of Naproxen: Naproxen is a widely prescribed NSAID and works extraordinarily well; however there are several undesirable adverse effects, which precipitate after an extended period of use, such as increase in blood pressure. A new drug has been derived from naproxen without this effect, Naproxcinod. From Diagram 19 it is possible to see that the hydroge Processes of Drugs Metabolism in the Body Processes of Drugs Metabolism in the Body Abstract Metabolism of drugs is a complex and major process within the body, occurring primarily in the liver. The aim of metabolism is to make the drug more polar to enable excretion via the kidneys. The basic understanding of drug metabolism is paramount to ensure drug optimisation, maximum therapeutic benefits and a reduction in adverse effects. Essentially drug metabolism is broken down into two phases, Phase I and Phase II. Phase I is concerned with the biotransformation of compounds, and then transferred to Phase II. However, for some drugs this is the end of their metabolic journey in the body, as they produce more polar compounds which are readily excreted. Phase II reactions are where compounds are conjugated to produce more water soluble compounds for easy excretion. Phase I reactions are dominated by the Cytochrome-450 enzyme superfamily. These enzymes are found predominantly in the liver, which is the major site of drug metabolism. However, drug metabolism is not localised merely to the liver, there are other major sites at which this process occurs. Some of these sites include the skin, lungs, gastro-intestinal tract and the kidneys; close to all tissues have the ability to metabolise drugs due to the presence of metabolising enzymes. The most important enzymes are the cytomchrome-450 superfamily, which are abundant in most tissues. Inactive drugs with the ability to reconvert to the active parent drug once metabolised to exert their therapeutic actions are defined as prodrugs. They are classified depending on the site of conversion and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within the body, compared to their active metabolites. Individual drug metabolism may be affected by variant factors, such as, age or sex. Drug metabolism can cause an increase in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this toxicity can occur in Phase I metabolism e.g. acetaminophen. However, in some circumstances toxicity occurs in Phase II e.g. zomepirac, polymorphism can also cause idiosyncracity of certain drugs to be toxic. 1.1 Phase I Phase one, otherwise known as drug biotransformation pathway is generally broken into oxidation, reduction and hydrolysis. A reaction under this phase involves an addition of oxygen molecule aiming to improve the water solubility of drugs. As the result some metabolites from this phase can be extracted immediately if they are polar enough however at times a single addition of oxygen is not sufficient enough to overcome the lipophilicity of certain drugs and hence their metabolite from this phase has to be carried onto phase II for further reactions. Major example of Oxidation: Accounting for roughly 20 complex reactions the most important oxidative metabolic pathway dominating phase I is the cytochrome-P450 (CYP450) monooxygenase system processed by C-P450. Located primarily in the liver CYP450 was found to be present in all forms of organisms, including humans, plant and bacteria. It is important to note that the function of CYP450 goes beyond drug metabolism but it is also involved in metabolism of xenobiotics, fat soluble vitamin and synthesis of steroids. With substrate specificity of more than 1000 and its ability to produce activated metabolites such as epoxide are the underlying reason for its dominance and importance in drug discovery. The general mechanism the CYP450 monooxygenase oxidation is: R + O2 + NADPH + H+ à   ROH + H2O + NADP+ (fig 2) From the above formula it can be this reaction is of NADPH (Nicotinamide adenine dinucleotide phosphate) and an oxygen molecule dependent. As mentioned above oxygen is important to increase the water solubility and in the same manner NADPH is also important for oxygen activation and source of electron. Also important for activation of oxygen is the presence of cystine amino acid located near the protein terminal carboxyl of CYP450. Among the 500 amino acid present in CYP450, cystine has proven to be most important as it activates the oxygen to a greater extend. This is due to the fact that it contains a thiol group as one of its ligand and it is the thiol which alerts the reactivity. Highlighting the numerous intermediate structures involved as well as function of iron, oxygen and proton (Figure) shows the catalytic conversion required for cp450 oxidation reaction to place. The binding of the substrate with low spin ferric CYP450 enzyme induces a change in its active site. This will effects the stability of the water ligand and will displace it (shown in the diagram from a-b). Containing a high spin heme iron the enzyme and substrate form a ferric complex. The change in electronic state will result in the release and transfer of one electron from NADPH via electron transfer chain (reducing ferric heme iron to ferrous state) and thus reduction of the complex. The second electron is transferred when the complex reacts covalently with the oxygen forming a new ternanry complex. Initially the complex is an unstable oxy-P450(diagram d), however this is reduced to produce ferrous peroxide by a loss of an electron. This intermediate is short lived and undergoes protonati on twice resulting in a release one water molecule. Out of the oxygen molecules released one in incorporated in this water molecule and the remaining into the substrate. Another method of forming the iron-oxo intermediate is via the peroxide shunt which elimited steps from C to F. Some of the common addition of oxygen molecule reactions which CYP450 dependent are known as epoxidation (of double bond), N-hydroxylation, oxygen/nitrogen/ sulfur dealkylation, s-oxidation, dechlorination, oxidative desulfurisation and aromatic hydroxylation. Note they all follow the same principle of adding oxygen molecule to the substrate. The diagram below provides an example of how these reactions are processed: Aromatic hydroxylation substrate mostly produces phenols such as that seen on figure 3. The production of Phenol can be either via a non enzymatic rearrangement or by Epoxide hydrolase and cytosolic dehydrogenase which will ultimately give rise a catechol. The position of hydroxylation depends greatly on the nature of the R- group attached to the ring; an electron withdrawing group will position the -OH group on the metha while the electron donating will position it on the para or ortha. Aromatic hydroxylation also involves a change in NIH shift, which involves the movement and shifting of the R group to an adjacent position during the oxidation. It is important to note that certain substrate for aromatic hydroxylation can also be oxidized via the aliphatic (C-H) hydroxylation. Under such condition the aliphatic C-H) hydroxylation will oxidize it. Aliphatic dehydrogenation can also occur involving electron transfer to the CYP450. Currently more than 50 CYP-450 has been identified in human, however the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand side clearly demonstrate just how much of drug metabolism is CYP450 3A responsibility in comparison to other, accounting for roughly 50%. Metabolism of drugs given orally are greatly determined by CYP450-3A primarily because this enzyme is present in both the liver and intestine and thus providing a barrier for all drugs before they can enter the systemic circulations, otherwise commonly known as ‘first pass effect. Upon entering the drugs are taken up via passive diffusion and/or facilitated diffusion or active transport into the entercocyte where they can be metabolized by CYP450-3A. They can once again be metabolized by the very same enzyme when they enter the liver (hepatocyte) ,which unlike the intestine in order to reach the systemic circulation it is unavoidable. Th is family of enzymes are also known to be cause of many serious adverse effects as they are influenced by diet and drug components, hence drug-drug and drug-food interactions is an important factor. Flavin monooxygenases Similar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major role in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also oxygen and NAPDH dependent, Flavin monooxygenases has much broader substrate specificity than CYP450. Once they have become associated with substrate the flavin monooxygenases is activated into 4ÃŽ ±-hyroperoxyflavin and unlike CYP450 the oxygen activation takes place without the need for substrate to bind to the intermediate. This pre-activated oxygen means that any compound binding to the intermediate is a substrate to be metabolized. The fact that this enzyme is able to remain stable and lacks any need for correct arrangement and disorientation of the substrate gives it ability to withhold all the energy required for the reaction to takes place and hence as soon as appropriate lipophilic substrate becomes available it starts the process immediately. Adverse side effects are rarely associated w ith these enzymes. The binding of oxygen to the reduced flavin is processed via a non-radical nucleophilic displacement. The substrate is oxidized via a nucleophilic attack by the oxygen that is located at end of 4ÃŽ ±-hyroperoxyflavin. This is then followed by cleavage of peroxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4ÃŽ ±-hyroperoxyflavin has been regained using NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times undergo reduction back to its original parent form. Alcohol dehydrogenase and aldehyde dehydrogenase These families of enzymes are both zinc containing NAD specific and catalyze the reversible oxidation of alcohol and aldehydes respectively. Grouped into 1-6 Alcohol dehydrogenase, are homodimer that exist in the soluble section of the tissue. It is involved in metabolism of some drugs such as cetirizine however it is more predominantly known as alcohol metabolism enzyme specifically ethanol, whether products of peroxides or that of exogenous (i.e administered drugs). It is important to note that although alcohol dehyrogenase is the main metabolic pathway for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulting in adverse side effects between alcohol and with certain analgesics drugs. Alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a longer half life and rapid absorption from the gut, methanol can result in series of unpleasant side effects and metabolic acidosis, hence highlighting the importance of alcohol dehydr ogenase. Similarly, aldehyde dehydrogenase catalysis the oxidation of aldehyde to its corresponding carboxylic acid. Class one of alcohol dehydrogenase plays a major role in detoxification of anti cancer drugs. Alcohol dehydrogenase is also involved in reduction pathway of aldehyde or ketone back to its pharmacologically active alcohol form. Monoamine oxidase and diamine Located in liver, intestine and kidney as few of its site, this membrane bound enzyme is divided into two classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deamination to aldehyde, these enzymes are flavin containing enzymes and within their cysteinyl residue the flavin is linked to the covalently bounded flavin via a thioether. Monoamine oxidase has several substrates, ranging from secondary to tertiary amines that have alky group smaller than methyl. The general mechanism for this enzyme is the two electron oxidation shown below: R.CH2.NH2 + O2 + H2O à   R.CHO + NH3 + H2O2 (fig 7) As it can be seen this reaction requires oxygen to react and a hydrogen peroxide is produced as for every â€Å"one molecule of oxygen is absorbed for every molecule of substrate oxidized† (Principle of drug metabolism, 2007). Proportional to the rate of oxygen uptake this is commonly used to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenous substrates such as noradrenalin while monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their common substrate is dopamine. Inhibition of monoamine oxidase has long been of an interest for scientist in treatment of several of illness such as depression. Present in liver, lungs and kidney as few of its locations diamine oxidase also catalyses the formation of aldehyde from histamine and diamines in the same manner. Reduction This pathway of metabolism is enzymatically the least studied in phase I and yet it plays an important role in metabolism of disulfides and double bonds of for example progestational steroids as well as dehydroxylation of aliphatic and aromatic compounds. In general ketone containing xenobiotics are more readily metabolized and eliminated via this pathway in the mammalian tissue. This is due to the fact that the carbonyl group is very lipophilic, thus the lipophilicity will be reduced and elimination is ensured as ketone is converted to alcohol. One of the major enzymes involved in this pathway is the NADPH cytochrome P450 reductase. Containing flavin adenine dinucleotide and flavin mononucleotide is an electron donor playing an important role in the metabolism of drugs such as chloramphenicol by reducing its nitro group. Hydrolysis As the name suggests this pathway uses water to cause a breakage of a bond. Major enzymes under this pathway are the amide and ester hydrolysis and hence amide and esters are the common substrates. Naturally esters are much easier targets to esterase hydrolysis than amides. A very common amide substrate is a local anesthetic, Lidocaine and an antiepileptic drug known as levetiracetam. Catalyzing ester and certain type of amides are the group of enzymes referred to as carboxylesterase. This enzyme hydrolysis choline like ester substrate and procaine. As a rule, the more lipophilic the amide the better it be accepted as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and slower to be hydrolysed and will usually be eliminated unchanged at a high percentage such as that for atropine, eliminated 50% unchanged. A very good example of esterase enzyme is the paraoxonase. The hydrolysis of substrate such as phenyl acetate and other acyl esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are imperative for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the carbon attached to the oxygen resulting in a formation of tetrahedral orientation. The presence of a hydrogen donor to the improvers the leaving group abilities is the final requirement. 1.2 Phase II (Second part of drug metabolism): Second part of drug metabolism, involves introduinh of new ionic chemicals on to the substrate (including the metabolites from phase I) in order to increase its water solubilyt for elimination. This phase is usually refered to as conjugation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major conjugation of phase II. Methylation is the transfer of methyl group to the substrate from cofactor s-adenosyl-L-methionine (fig 9). S-adenosyl-L-methione is an active intermediate that receives a transferred methyl group from methionine after its linkage with ATP in presence of adenosine transferase enzyme. It is this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group becomes attached to the sulfonium center marking â€Å"electrophilic character† (Principle of drug metabolism, 2007). Depending on the functional group present on the substrate Conjugation via methylation is broken down to nitrogen, oxygen and sulfate methylation. O-methylation O-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to ‘Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to size of the substituted group, the larger it is the slower the rate of reaction degree of acidity of the catechol group itself. N-methylation Naturally this reaction has substrate specificity of amine, involving however primary and seconday only. Unlike the above reaction, N-methylation consists of several enzymes, all of which are categorized in accordance to the specific type of amine substrate which they catalyze. Enzymes such as amine-N-Methyltransferase, nicotinamide-N-methyltransferase and histamine-N-methyltransferase are few examples. Despite the substrate specificity all the enzymes involved do however follow the same principle of transferring methyl fromcofactor s-adenosyl-L-methionine to the substrate. With drug substrates such as captoril, reactions of N-methylation can be broken down into two distinct types as illustrated in Fig 11. Reactions that have a low pharmacological significant yield an ineffective n-methylation as the substrate and the product have a same electrical state thus the metabolites are usually less hydrophilic than parent. As it can be seen from fig 7a, in these reactions one proton is exchange for a methyl group. On the other hand a more hydrophilic product and an effective reaction of detoxification is achieved with pyridine type (nitrogen atom) substrate. These substrate will result in a creation of positive change on the product (fig 7b) rather than an exchange process. Sulfate and phosphate conjugation Sulphate conjugation is one of the most important reactions in biotransformation of steroids, effecting its biological activates and decreasing its ability for its receptor. Nucleophilic hydroxyl groups such as alcohol and phenol, primary or seconday amine and drug containing a SO-3 group are the common substrates for this pathway. Generally sulphate are transferred via a membrane bound enzyme named sulfotransferase (located in golgi apparatus) from their cyclic cofactor 3-phosphoadenosine 5 (shown in fig 8 ) to substrate. 3-phosphoadenosine 5 is formed in a reaction between adenosine triphosphate and inorganic sulfate where the sulfate/phosphate group are bonded via a anhydride linkage which gives rise an exothermic reaction when broken, hence providing the energy for the reaction. In human there is two class, SULT 1A- 1E and SULT 2A-2B, each of which will have different specificity yet with overlaps. This enzyme acts on both endogenous as well as exogenous compounds as long as they possess an alcohol (less affinity with varying product stabilities) or phenol (products are stable arly sulfate esters with a high affinity). Substrates are generally of medium sized, highly ionized and hydrophilic, hence excreted easier via urine. The rate of this pathway is determined by the lipophilicity and nature of amino acid present on the substrate. Interestingly phenol is also of an interest for the Glucoronic conjugation pathway and are metabolized by this when they are at high concentration and 3-phosphoadenosine 5 becomes rate limiting. The sulfate conjugation will produce ester sulfate or sulfamide some of which will undergo further heterolytic reaction leading to electrophilic substrate and hence toxicity. Unlike the sulfate conjugation the phosphate conjugation is less common unless the drug in question is anticancer or antiviral. Catalyzed phosphotransferases. conjugation The most important and major occurring metabolic pathway of phase II is the glucoronic conjugation, accounting for the largest share of conjugated metabolite in the urine. This pathway is important due to the fact there is a high availability of glucucronic acid, huge substrate specificity and the wide range of poorly reabsorbed metabolite. The glucoronic conjugation takes place as the glucoronic acid is transferred to the acceptor molecule from its cofactor uridine-5-diphosphh-alpha-glucoronic acid (fig 9 ) of which glucoroniuc acid is attached in 1 ÃŽ ± configuration. However products produced are in ÃŽ ²-configuartion. This is due to the nucleophilicity of the functional groups of the substrate. To be able to undergo this pathway of metabolism the functional group of drugs in question must have nucleophilic characteristics. Generally the drug that are at high affinity for this pathway is firstly phenol (paracetamol) and then alcohol (primary, secondary or tertiary) suc h a morphine. The transformation of the drugs involves a condensation reaction and hence release of water, while the conjugate replaces the hydrogen on the -OH group. Present in the ER uridine-5-diphosphae-alpha-D glucoronic acid is produced due to oxidation of carbon position six of UDP-ÃŽ ±-D-glucose. Interaction of this co factor with the substrates is catalysed by one the two classes of UGT1 or UGT 2, present mostly in liver however still found in brain and lungs. As this pathway produces a wide variety of procucts, work has been done to divide them into four groups of O/S/C/N glucoronides, with the o-glucoronides being the most important forming a reactive metabolite known as acyl-glucuronides. Generally drugs containing functional groups such as carboxylic acid, alcohol and phenol give rise more examples shown in fig 10. Acetylation Involving a transferring of an active acetyl linked via a thioester bridge to acetyl-coenzyme A (fig below) to a nucleophilic function group of substrate this metabolic pathway mainly occurs in liver involving amino groups of medium basic properties. One of the common drug metabolized by this pathway is the para-aminosalicly. Large group of enzymes known as acetyltransferase are enzymes involved in catalyzing this pathway, among these are the aromatic-hydroxylamine O-acetyltransferase and the arylamine N-acetyltransferase. Interestingly, genetic polymerization of acetylation function has meant that the rate of reaction and occurrence of toxicity will differ in accordance to the polymers. Fast acetylation will have result in a fast conversion and elimination while slow acetylators will have the opposite effect and will lead to build of unconjugated compounds in the blood and hence leading to toxicity. Conjugation with co-enzyme A Commonly using this pathway are the carboxylic containing which are activated into an Intermediate and eventually forming a acetyl-CoA conjugate It is important to note that primary metabolites from this reaction do not show up in vivo and only in vitro, however some of its secondary and stable metabolites that have undergone further reactions do. A factor that seems to cause problems with this pathway is the occurrence of toxicity, rare but serious as it the conjugates interfere with normal endogenous pathway. A common example was seen with NSAID which have now been long removed from market. Conjugation with amino acid This metabolic pathway is the most important for carboxcylic drugs where they form conjugate with the most common amino acid, glycine. Products are non-toxic (with no exception) and more water soluble than their parent compound. The drugs first become activated to the co- enzyme A before forming an amide or peptide bond between its carboxylic group and amino acid. The enzymes that facilitate this reaction are those of N-acyl transferases, such as glutamine N-acyltransferase. Carboxylic substrate for this pathway are also of an competition for the glucoronic conjugation, at high concentration if drugs glucoronic conjugation is preferred due to high availability, while at low concentration conjugation with amino acid is used for the metabolism. Conjugations with Glutathione Conjugation with glutathione has a wide variety of substrate specificity; this is partly due to the fact that in vivo glutathione exists as in equilibrium between its oxidised and reduced form hence enabling it to accept a wider range of substrate. The reduced form of glutathione is able to act as a protecting agent as it removes free radicals while the oxidised form oxidizes peroxides. A thiol, the glutathione contains a tripeptide and with a pka of 9.0, allowing it to be an excellent nucleophile agents, due to the increase in the ionization due to the thiol group. As the result of these electrophilic groups are easily attacked, usually on the most electrophilic carbon (commonly sp3 or sp2 hybridised) that contains the functional group. Enzymes responsible for catalyzing these reactions are known as glutathione transferase, seven of which are found in human. They also serve an important role apart from catalysing as upon binding of the active side with the glutathione will results i n a decrease in pka value and hence an increase in acidity (the thiol is deprotonated thiolate), thus enhancing the nucleophilic abilities. Depending on the substrate in question the conjugation with glutathione can be divided into forms, nucleophilic substation or nucleophilic addition. During the nucleophilic addition, an addition followed by an elimination reaction occurs. Attack occur at the activate electron lacking CH2 group, which the glutathione substitutes as it becomes added on to the carbonyl as shown in fig 12. Nucleophilic substitution reaction is much more common with xenobiotic than drugs although it is seen with chloramphenicol, where its -CHCL2 becomes electrophilic due to a electron withdrawing group. One of the most important conjugation in relation to glutathione is with epoxides giving rise to a protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via dehydration catalyzed by acid giving rise to a GSH aromatic conjugate. As a final metabolite a mercapturic acid (a condensation reaction exerted by urine) as shown in (fig below) is formed via a series reactions including cleavage and n-acetylation . 2.1 Metabolism in the liver When a drug can be cleaved by enzymes or biochemically transformed, this is referred to as drug metabolism. The main site of drug metabolism within the body occurs in the liver, however, this is not the only site in which metabolism of drugs occurs, this will be discussed later. The liver ensures drugs are subjected to attack by various metabolic enzymes; the main purpose of these enzymes is to convert a non-polar drug into more polar molecules, thereby increasing elimination via the kidneys. The polar molecules formed are known as metabolites, these lose a certain degree of activity compared to the original drug. Metabolic enzymes, cytochrome P450 enzymes enable the addition of a polar compound to particular drugs, making them now polar and more water-soluble. On the other hand, some drugs may become activated and then have the desired effect within the body, these are referred to as pro-drugs; and will be considered in greater detail later. Drug metabolism is split into two stages known as Phase I reaction and Phase II reaction, both of which have been discussed earlier. Certain oral drugs undergo a first pass effect in the liver, thereby reducing bioavailablity of the drug. This can lead to numerous problems, such as, individual variation that can then lead to unpredictable drug action, and a marked increase in metabolism of the drug. These problems related to the first pass effect may hinder the desired therapeutic effects from being fully achieved. Many drugs undergo first pass metabolism, previously seen as a disadvantage, but now due to a greater understanding of hepatic metabolism it can be used advantageously, for example Naproxcinod. Naproxcinod is related to naproxen, which will be discussed below, we will also be examining the metabolism of propanolol. Naproxcinod is derived from the non-steroidal anti-inflammatory drug (NSAID), Naproxen. First we will examine the metabolism of Naproxen (6-methoxy-a-methyl-2-naphthyl acetic acid). Naproxen is a widely used NSAID, possible of blocking both cyclo-oxygenase isoforms 1 and 2, therefore making it a non-selective inhibitor of these isoforms. Rheumatoid arthritis and osteoarthritis are the main reason for use of naproxen, which is administered orally as the S-enantiomer. This particular drug is well absorbed by the body and is metabolised in vivo to form various metabolites, the major metabolites being naproxen-b-1-O-acylglucuronide (naproxen-AGLU) and desmethyl-naproxen (DM-naproxen). Naproxen is conjugated in a Phase II reaction with glucuronic acid to form an acyl glucuronide (Diagram 2), with the intermediate being DM-naproxen. Usually conjugation reactions produce inactive metabolites, however with glucuronic acid the metabolite formed can occasionally become active. This reaction is facilitated by the superfamily UDP-glucuronosyl transferase (UGT) enzymes. The major UGT isoforms found in the liver are: 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7 2B10, 2B15, 2B17 and 2B28. The isoform 2A1 is found mainly in the nasal epithelium, while 1A7, 1A8 and 1A10 are only localised to the gastro-intestinal tract. UGT acts as a catalyst enabling glucuronic acid to bind to naproxen at the carboxylic acid group via covalent bonding. It has been found that all UGT isoforms contribute to the conversion of naproxen to its metabolite naproxen-AGLU, except UGT-1A4, 2B4, 2B15, and 2B171. This reaction produces a highly polar glucuronic acid molecule bound to naproxen. Its main mode of elimination is through the urine. The next major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An unstable metabolite is formed during this process, however it is hydrolysed immediately to DM-naproxen. The enzymes involved in this reaction are cytochrome P450 1A2 and 2C9 from Phase I. Once DM-naproxen has formed it is glucuronidated with the help of UGT enzymes 1A1, 1A3, 1A6, 1A9 and 2B7 and converted to its acyl glucuronide. UGT-2B7 is a high affinity enzyme and so has a high activity in this process, as does UGT-1A6. UGT-1A4, 2B15 and 2B17 do not contribute to the acyl glucuronidation process1. DM-naproxen is also converted to phenolic glucuronide; this is formed by the UGT enzymes 1A1 and 1A9. Enzymes UGT 1A3, 1A6 and 2B7 appear to play no part in this reaction. UGT 2B7 works well in glucuronidating the carboxylic acid moiety in particular drugs; however it is unable to glucuronidate the phenolic group, so for this reason is not involved in forming phenolic glucuronide. The aim of hepatic metabolism is to ensure metabolites are made more water-soluble hence easily excreted. All metabolites formed from naproxen are water soluble and easily eliminated from the body. However, there are two metabolites that have been found to be far more water soluble, these are naproxen-AGLU and acyl glucuronide2. Huq (2006) explains this is due to the high solvation energy of both metabolites compared to naproxen and its other metabolites. Metabolites of Naproxen: Naproxen is a widely prescribed NSAID and works extraordinarily well; however there are several undesirable adverse effects, which precipitate after an extended period of use, such as increase in blood pressure. A new drug has been derived from naproxen without this effect, Naproxcinod. From Diagram 19 it is possible to see that the hydroge