Socrates The Afterlife Essay Example for Free

Socrates The Afterlife EssayRead selections from The Phaedo, available in this weeks Electronic Reserve Readings. Focus on paragraphs 107 to 115a (pp. 437444). spare a 350- to 700-word essay on the followingWhy does Socrates not fear death?What are his views on death and the afterlife?Do you agree or disagree with Socrates on this topic?Using the Socratic method and The Good Thinkers Tool Kit, formulate at least one call into question you would ask Socrates about his views on the afterlife.Socrates view of the afterlife is a little difficult to assess due to the fact that there are not developed written works by Socrates. The only works about him are by other people. Socrates view of death came up in a conversation when asked by Cebes about the poetry he was working on. The discussion starts with the question suicide. Socrates thesis was the one aim of those who practice philosophy in the proper modality is to practice for expiry and death. He also defines death as the sepa ration of body and soul. All this lead to Socrates conclusion about death which is, upon dying a philosopher is most likely to obtain the wisdom which he has been seeking his whole life. Socrates also had an interesting view of the afterlife. Since being dead and being vivacious are opposite states, and dying and coming-to-life are the two opposite processes between these states, coming-to-life must balance out dying. Socrates also recalled an ancient theory basis just as the souls of the dead in the underworld follow from those living in this world the living souls come back from those of the dead.He concluded that everything that dies must come back to life again. Socrates made a strong argument with valid points that cannot be dismissed. If the two opposite processes did not balance each other out, everything would lastly be in the same state for example, if increase did not balance out decrease, everything would keep becoming smaller and smaller. Another prime example of this is the Yin and Yang which is a Chinese philosophy and culture which based its principle in that all things exist as inseparable and contradictory opposite, for example female-male, dark-light.

Market Segments Essay Example for Free

Market Segments EssayApple is marketing to people who have a few characteristics.1) Middle/ speed income folks who are willing to pay a bit more for a better user experience. paying 500 more for a estimator is not a huge deal if you have a decent income.2) throng who like to have fun with technology. No other platform offers as many entry level tools (the whole iLife bunch and more). This includes people who like to shoot a lot of digital photos or video. Its the whole digital hub concept. heap are starting to buy into it.3) Music enthusiasts and fans ages 12-35.4) Professionals in media and design.The first two groups do oerlap, but its a huge market. Way bigger than 5% or whatever. Apples problem is not really pricing. These are the same people who pay $500 to get seats that warm up your behind. Apples problem is the status quo. People who should consider macs dont, because of a stigma of incompatibility that developed in the 90s.Apples market share and success will grow in the next ten historic period for the simple reason that our generations X and Y who have been exposed heavily to the internet werent using computers much during the compatibility days But anyway, the compatibility problem dies when the people who gestate in it are not young anymore.Market SegmentationThe market segmentation includesDemographical bases.Geographical bases.Behavior bases.Psychographic bases.2.1 Demographical bases (age, family size, life cycle, occupation) smell into Apple, the Demographical market segment is productive because they are developing products on the age, life cycle, occupation of the people. They are distributing their products into various places and the PCs are categorized on age, family size, for example they would have more games and entertainment in the PCs for the kids and a professional PC with all the latest softwares. 2.2 Geographical bases (states, regions, countries)Looking into the geographical bases of Apple they have established their business all over the world like U.S., South America, Europe, Japan, and Australia. Recently Apple chose to implement a vertical growth strategy and began expanding their own retail stores. The company also sells its product via third-parties dealers, or via internet through their own website or through the iTunes online music stores.2.3 Behavior bases (product cognition, usage, attitudes, and responses) In this market segment Apple providing good product knowledge to the customers by advertizing on search engines, T.V. as they have a very good brand image. Using this brand image they are continuously coming up with new ideas and products and attracting the customers. Apple has got a very good response rate as many of the customers are looking for new designs and advance(a) products which Apple is successfully delivering. 2.4 Psychographic bases (lifestyle, values, personality)Looking into Apple the psychographic market segment is successful because they are developing products on the lifestyle of the people such as mac book for the younger generation. Apple having a very good brand image has very good value for its products as they are different and innovative. Looking into the personality (style) sector Apple is providing their products with different colors for the people who like fancy colors.

Corporate Management of Starbucks in Action

Corporate Management of Starbucks in ActionAssignment 01 Explain how Starbucks was able to suffice its operations about the globe, was it successful in perform its operations with existing operations and there is any enquire for Starbucks to move forward for joint ventures and strategic adhesion.IntroductionIn 1971, Starbucks started their journey and now they ar direct(a) to a greater extent than than 50 countries in the world. Their total number of store is rough 16,706 in 16000 locations around the world. nigh of them 8850 stores atomic number 18 operated by the political party and the respire of them ar licensed store.1Globalization is a movement toward economic, financial, interchange, and connections integration spherically. In broader sense, globalisation implies free transfer of capital, beloveds, and services across around the globe. In work context, cooperation and competitiveness both are embraced by globalization. Major perceptive of depending on each otherwise and shared responsibilities at work across company and nationally boundaries come from idea of cooperation. The awareness developed by the idea of competitiveness that cooperation without motivation is fruitless to failure and that only practical encouragement can constant suppuration and growth beat a prevalent way of life.( Globalization of stemma practice and theory by Abbas Ali)Theory of international tradeThe supersede of capital, goods, services across international borders or territories is basically international trade. The crucial to the persistence of globalization is in increasing of international trade. The lacking of international trade and it caused limited goods and services produced within their own borders. on that point are different model of international trade for the chore.Ricardian modelRicardian model mainly take in consideration on comparative advantage it is one of the most important concept in international trade theory. In this model, g ive importance on countries specialization in producing most excellent. The major drawback of this theory is that does not believe factor endowments care labour and capital with respective to country.Heckscher-Ohlin modelThe Heckscher-Ohlin theory focuses that resources needed for countries producing and exporting goods. Accoding to Heckscher-Ohlin theory, a country should used most plentiful and cheapest resources in producing and exporting goods. It has some core assumptionCapital and labour flow freely between sectorsLabour and capital whitethorn vary between two countries (difference in endowments)Free tradeTechnology is the same diagonally countries (long-term)Tastes are same.i original situation and performance of StarbucksStarbucks has created a global chain in market industry around the world. This company is operate more than 50 countries and their estimated turnover is nearly $5300 million in each year. Their main product is coffee and demand of the product is increa sing globally. Starbucks cafe is real reputed and around 30 million customer visit in each week. This is one of the credit sides for the Starbucks.2Currently Starbucks seems a rising part of their business sector and is going to become a leading global organisation in the world. lodges global market capturing and their effectiveness in ventures made them successful in achieving organisational goals. There are many countries where are run their business. These are Australia, Taiwan, Thailand, United Arab Emirates, Egypt, United Kingdom, and the United States, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Malaysia, New Zealand, Oman, and Peoples Republic of China, Philippines, Qatar, Saudi Arabia, Singapore, South Korea, and Switzerland. Their way of attracting customer attention is very important for the business to become worldwide mug that actually helping them to manage partnership of reputed company. This is positive side for Starbucks to move in future and it s international market developments. This is one of the strengths for to be a foremost coffee retailer around the world.3Human resource charge evaluationHuman resource management plays an important role in the organisation by managing human resource inside the organisation. In order to improve skills of employees requires learning. It does not matter how the candidate is, they can be best or 100% qualified. It can be solved by human resource management by implementing learning management system. (Beard sanitary Holden, 1997). Every employee should have the knowledge about the various processes that they can develop skill in specified area. They need to respond 100% in their job. Thats why human resource management and normal management need to cooperate with each other. The companys principle rules mainly focus on employees and how to guide them according to mission of the organisation. Moreover, Starbucks gives facilities to their employees by creating good work surround as well a s treat with them with prosperous. Starbucks too provide training to their employees for the enhancement of knowledge, attitudes and skills that they need to perform task supplied by the employer. Starbucks also motivate their employee to perform task well. They also informed to their employees about everything. Employees are also capable to work nether pressure easily. They also evaluate their employees through various programs as well as developed their employees to compete globally. When they recruit people in the altogetherly then they must provide training for them.4External environment analysis (opportunities and threats)Starbucks is operating in more than 30 countries around the globe including United States by Joint venture, licensing and entirely owned. For subsidiary company needs a lot of training, supervising, management assistance and technology transfer for the partner. Product innovation is very effective for them and it came out with sassy products. Starbucks als o focused on diversification. It also entered into alliances with different company to serve coffee.International Business Expansion Strategies of StarbucksSubsidiary Starbucks Coffee International Inc. started its journey as subsidiary of Starbucks which was formed in 1995.As a subsidiary it is conjectural to introduce improvement challenges beyond North America which combines stores planning and financing, logics and operational management, merchandising of business, improvisation of skilled and matured mangers of Starbucks international (Kotha and Glassman 2003) and introducing new strategy of business development. The international courses of expansion and strategies are managed by the International Starbucks as a separate owned subsidiary. Two strategies are followed when introducing in a brand new market. Licensing and joint venture are the chosen two. International Joint Venture The joint venture introduces a strategy towards managerial liabilities .A strategy for new busin ess entity comes with shared ownership which is implied by two or more farms. The agenda of venture strategy is mostly for short time period with some grumpy quoted mottoes. Starbucks (Briscoe and Schuler 2004) is an example of adopting such strategy in business internationally.(Schuler et al 2003) Two or more parent farms which deeply invest resources as well as financial momentum to convince particular aims that introduced International joint ventures(IJVs) which are different organizational entities both in legal and economical perspectives. Joint venture introduces a strategy towards managerial liabilities .A strategy for new business entity comes with shared ownership which is implied by two or more farms. The agenda of venture strategy is mostly for short time period with some particular quoted mottoes. Starbucks (Briscoe and Schuler 2004) is an example of adopting such strategy in business internationally.(Schuler et al 2003) Two or more parent farms which deeply invest reso urces as well as financial momentum to convince particular aims that introduced International joint ventures(IJVs) which are different organizational entities both in legal and economical perspectives.Manufacturing and foreign joint venture licensing and joint venture franchising and joint venture are example of combination market entry strategies. Licensing and joint ventures are the strategies that applied with Starbucks international. Mostly the stores located in USA are owned under corporation, other than USA the stores are under corporation or owned partially in joint ventures (Alexandrides and Bowers2005).Licensing Manufacturing or marketing someones good(s) for international business success depends on licensing rights. The basic way of unveiling in new location of business through showing positivity to the binding of contract .Such as licensing the goods, technology help to other farm and absolute services. In return for royalty payment the corporation sells a particular r ight to introduce and advertise the good under these criteria. Starbucks does not need to narrow any monetary actions for partnership investment under this particular method. It is an amicable way to get access in international market. Starbucks can also proceeds from granting license to a licensee that is more familiar with the market.5Entry strategies in actionStrategic alternative options for StarbucksHaving learnd the external and internal forces of Starbucks it is now possible to generate tierce possible future strategic decisions. These strategies will be analysed thoroughly before one of them is recommended as the best way forward. The options I have chosen to analyse are Diversification, Mergers and Expansion. If a business is in diversification, it starts making new products or contribution new services. Businesses can diversify in two ways colligate and unrelated. I propose Starbucks attempt related diversification by this I mean diversification bounceing some connec tion with the organisations activities.Starbucks is successful in appropriate development method or notThe path chosen by Starbucks is the appropriate way to expand the business globally considering every aspects and expertise of the business. Strategy like licensing and joint venture helped to uplift the quality and service of Starbucks. As mentioned earlier Starbucks adopts the partnership method with a local experienced farm. This method delivers vast opportunities to scrutinise the local consumers more closely. As a result it was easy to cope up with the local consumers expectations and inject success in the business.Alternative methods might be suitable for the companyStrategy like franchising or cross- interchange can be elected by Starbucks when entering in a new region. It is more licensing alike. Company like McDonalds which represents the perfect example of franchising. In the scenario of McDonalds, the real company allows franchising terms to other current farms to deliv er their goods. Other than North America every business of Starbucks is owned partially. On the other hand, McDonalds is a representation of franchising which is owned by separate corporations.Starbucks may adopt method like franchising. In the franchising method, the relation is more parallel between both parties. In this strategy the franchisee is more controlled by the franchisor.Starbucks use of different methods in different marketsWhile entering markets the strategy may vary place to place. Before making any further entry to a new market a company must keep real countable factors to make the investment successful. Internal as well as external facts should not be ignored. Starbucks does assessments like ethical, economical, sociological, industrial positioning and other factors. There are three important groups of facts which are assessed prior accessing in a new market. Environment of business in that very country, environment of home country and important factors of company are the must do three. Political stability of business, conditions like macroeconomics, potentiality of resources, size of the market and internal economical relation are included in host country environment. Factors like expansion of foreign economy, conditions of market and government positivity towards foreign exchange are included in host country environment. Resources of company and capabilities of the farm are included under company specific environment.Development Mode can be combined with other Expansion MethodsStarbucks believes to accumulate different methods to inject success in the business. It adopts the licensing strategy to ensure the quality of the product and services are good enough to enrapture the consumers. Licensing is the way of expanding and at the same time joint venture applies for the growth or development of the business.Starbucks scrutinises the external countable factors at the entry level of new locations. On the basis of three must do assessments it considers the strategies that should be undertaken. The best locations and targets are chosen on the result of the analytical assessments. The success of the business depends on the entry level strategy and operation of assessments. The success of the business does not only a result of best location it is also a accumulated events of proper planning, entry level operation and funding. The home country methods generally come along with the strategies named Corporate and business level.6Starbucks joint venture and strategic allianceStarbucks need for joint ventures and strategic alliance to move forwardIn 2004, Starbucks was operating in more than 25 countries but now they are operating more than 50 countries around the glove. There are many advantages in being part of a joint venture. Through joint ventures it is possible to tack together knowledge about the countrys culture, language, political system, and business systems.7They are already holding strong joint ventures with good strategic alliance in different countries in the world. They have established strong reputed brand image of their product. They are now getting full culture support from different countries by understanding the need for people, which reflect their good strategy in business. If we compare with the current market situation, we found that their consumptions of coffee is around 50% in Europe with in whopping tradition of coffee consumption in people And they are good in gaining market share. In Asian market coffee consumption is around 15% with spirited market impending. Starbucks dont need joint expansion of ventures because of high dominating power in current international market with established brand name and image. They have huge manpower as well and high standing reputation in the market and they dont need to spend more on advertising.8Starbucks are now as a top level company in the world and also they are paying high salaries and benefits to their employees. Further if they wi ll go for joint venture their might have the possibility of losing customers. Employees who they are working now do not feel to draw because their way of treating is very friendly with employees by maintaining high standard. They already have strong strategies and good product innovation system because of good holdings in the market. Starbucks are now selling ice cream outside of their different stores and super markets they are getting good response from there, just because of their established brand name.Starbucks are continuously maturation their strategies for running business in different countries around the globe and with high effectiveness. They are also spending more on apprise chain recruitment and payment to customer service. Starbucks are now finding new locations for the business and their business plans, mission, aims and corporate social responsibilities these all they doing from the part of good strategy they have. Without these they affectation move forward and cannot be competitive in the market as well.Factors that can lead to Starbucks successInnovationThrough inducing of environmental friendly productsCustomer safety maintainStore facilities should be improvedSome steps should be taken on-Need employee motivation through incentives and job satisfaction as well. The location of their company must be strategic. They also need to improve corporate social responsibilities though helping farmers in their livelihood as well as their houses, irrigation system etc. The company have focus on pricing strategies by comparing demand of product. They will have to focus on neglected customer and need look for on tea speciality market.9ConclusionStarbucks has now become leading multi-national company in the world by operating more than 50 countries in the world though establishing a leading global brand. Globally they are established and running their business effectively. They also change the concept of coffee shop into different manner like it c an be meeting place, dating place or business place.My researchIn 1971, Starbucks started their journey and now they are operating more than 50 countries in the world. Their total number of store is about 16,706 in 16000 locations around the world. Most of them 8850 stores are operated by the company and the rest of them are licensed store. In 2004, Starbucks was operating in more than 25 countries but now they are operating more than 50 countries around the glove. There are many advantages in being part of a joint venture. Through joint ventures it is possible to realize knowledge about the countrys culture, language, political system, and business systems. They are now getting full culture support from different countries by understanding the need for people, which reflect their good strategy in business. If we compare with the current market situation, we found that their consumptions of coffee is around 50% in Europe with in big tradition of coffee consumption in people And the y are good in gaining market share. In Asian market coffee consumption is around 15% with high market impending. Starbucks are now as a top level company in the world and also they are paying high salaries and benefits to their employees. Further if they will go for joint venture their might have the possibility of losing customers. Employees who they are working now do not feel to leave because their way of treating is very friendly with employees by maintaining high standard. They already have strong strategies and good product innovation system because of good holdings in the market. Starbucks are continuously developing their strategies for running business in different countries around the globe and with high effectiveness. They are also spending more on value chain recruitment and payment to customer service. Starbucks are now finding new locations for the business and their business plans, mission, aims and corporate social responsibilities these all they doing from the part of good strategy they have. Without these they cant move forward and cannot be competitive in the market as well. To be successful in future Starbucks should focus on employee motivation through incentives and their job satisfaction as well. The location of their company must be strategic. They also need to improve corporate social responsibilities though helping farmers in their livelihood as well as their houses, irrigation system etc. The company have focus on pricing strategies by comparing demand of product.

Triangle Love Intimacy

Triangle fare IntimacyTriangle of LoveRobert J. Sternberg, psychologist and dean of the Tufts School of Arts and Sciences proposed a triangular theory of approve that suggests that thither are one-third components of love intimacy, passion, and commitment. unlike combinations of these three components result in different typesetters cases of love. For example, a mixture of intimacy and commitment results in compassionate love, sequence a mixture of passion and intimacy leads to passionate love. Sternberg often said, relationships built on two or more elements are more enduring that those base upon a single component Tufts p 19. Sternberg uses the term over(p) love to describe a combination of intimacy, passion, and commitment. While this type of love is the strongest and most enduring, Sternberg suggests that this type of love is rare. He wrote that even as a teenager he was intrigued by the mystery of why some relationships succeed while others fail. This is why former(a) in his academic career he developed an explanation, which he calls the triangular theory of love. His theory is based on the thoughtfulness that love consists of three components . . . intimacy, passion, and commitment. Different combinations and fortes of those three ingredients, Sternberg says, produce different kinds of love. Tufts p. 20Intimacy is the feelings in a relationship that promote closeness, bonding, and connecting with one another. Passion is what drives the romance, physical attraction, and sexual consummation in a loving relationship. Commitment consists of two farewells. The first is a short-term aspect in which you make the decision that you love another person and the second part is the long-term aspect in which you decide to commit to a long-term relationship and maintaining the love for that person over a long period of judgment of conviction Everything2. Sternberg also gives a detailed explanation of the types of love. Infatuated love, for example, is all pas sion, without intimacy or commitment. Romantic love has passion and intimacy just now lacks commitment. friendly love, he says, results when we have only intimacy and commitment, as in a long-term deep friendship. The kind of love that embodies all three components he calls consummate love Tufts p.21. Sternberg uses the triangle to describe different way we evolve to being in love. Each side of the triangle represents the proportion of each component with prise to the other two. The shape of the triangle that Sternberg uses is supposed to symbolize the balance between intimacy, passion and commitment, because it is equal on all sides. This is the kind of love we all desire for at one point and time. It is also the kind of love we tend to associate with living a life full of love and happiness. Sternberg acknowledges that few charitable relationships can maintain this perfect balance indefinitely, yet many relationships succeed in the face of enormous obstacles because both part ies highly value consummate love, try it out and work hard to maintain it. Tufts p. 21Sternberg wanted his theory of love to show us true love should develop, but it also meant to be apply as to show us how we can develop loving and caring relationships with everyone that is apart of our life. In his study of human relationships, Sternberg discovered that mates tended to be happier when they had more of the three components of love. And it helped if their love triangles matched in size and shapethat is, if the amount and kind of love each partner felt for the other was about the same. Tufts p. 21I think that the love triangle is great. When the intensity of love shared by two people is great, so is the area of the love triangle and vice versa. However, the greater a circumstantial component of love, like passion, the further the point from the center of the triangle will be to that component. This is why the shape of the love triangle is reliant on the strength of the different w orkings of love. The shape of the triangle will and should evolve over time. We may achieve such perfect forms of love as consummate love, but we all know that perfect of love is hard to maintain over time because to sustain it, we must nourish all of its components. The more a couple works on keeping the three components of consummate love in balance and nourished, the more likely such a love will be maintained for a long period of time. Love its self is so strong. I have been in love a few times. When I did this typography assignment I realize that I was not really in love until I met my husband. I took the triangle and compared the components to my past relationships and there is no resemblance to what I have now. In society today, when someone mentions the word Love it is guaranteed that at least half the people surrounding you will shudder. Whether it is through observation or experience, people have come to learn that love is far from being the ideal state in which one shoul d live in and, for that take many choose to stay away from it. It is known to break hearts, to hurt feelings and, believe it or not, it truly is not always happily ever after. Yes, Love does have its positive points. It is thrilling and exciting when youre in love, it is sometimes even euphoric but the argument here is not whether Love is good or bad for you. You and only you can make that decision.Works CitedSternberg, Robert J. 2007. Happily ever after, Tufts Magazine 14 3) 19-23.http//www.everything2.com/index.pl?node=emotion

Processes of Drugs Metabolism in the Body

Processes of Drugs Metabolism in the bodyAbstr flakeMetabolism of medicates is a complex and study movement deep down the body, occurring primarily in the liver. The aim of metabolic process is to make the dose much(prenominal) frosty to enable excretion via the kidneys. The basic abjectstanding of drug metamorphosis is paramount to ensure drug optimisation, maximum healing(predicate) benefits and a reduction in unbecoming effects. Essenti wholey drug metabolic process is broken down into twain anatomys, seduce I and Phase II. Phase I is c oncerned with the biotrans com smear of compounds, and then broadcastred to Phase II. However, for rough drugs this is the end of their metabolic journey in the body, as they adduce more paired compounds which be readily excreted. Phase II answers be where compounds argon conjugated to produce more pissing meltable compounds for easy excretion. Phase I receptions atomic number 18 dominated by the Cytochrome-450 en zyme superfamily. These enzymes atomic number 18 fix predominantly in the liver, which is the study site of drug trans nameuration. However, drug metabolic process is non localised merely to the liver, there argon other study sites at which this process occurs. Some of these sites intromit the skin, lungs, gastro-intestinal tract and the kidneys close to tout ensemble tissues get hold of the cleverness to metabolise drugs referable to the presence of metabolising enzymes. The nigh strategic enzymes ar the cytomchrome-450 superfamily, which argon abundant in about tissues.In energetic drugs with the energy to reconvert to the spry enkindle drug once metabolised to exert their redress actions ar defined as prodrugs. They atomic number 18 classified depending on the site of vicissitude and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within th e body, compargond to their brisk metabolites. Individual drug metabolism whitethorn be affected by variant factors, such as, age or sex. Drug metabolism can cause an maturation in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this perniciousness can occur in Phase I metabolism e.g. acet aminic chemical multitudephen. However, in some set toxicity occurs in Phase II e.g. zomepirac, polymorphism can overly cause idiosyncracity of received drugs to be toxic.1.1 Phase IPhase unmatchable, differently know as drug bio change nerve tract is princip every(prenominal)y broken into oxidization, reduction and hydrolysis. A reaction under this phase involves an addition of root O tittle aiming to improve the water solubility of drugs. As the result some metabolites from this phase can be extracted immediately if they are charged enough moreover at measure a single addition of free radical O is non sufficient enough to overcome the lipophilicity of indisputable drugs and thence their metabolite from this phase has to be carried onto phase II for get along reactions. study example of OxidationAccounting for roughly 20 complex reactions the more or less substantial oxidative metabolic course dominating phase I is the cytochrome-P450 (CYP450) monotype Oase carcass touch by C-P450. Located primarily in the liver CYP450 was found to be redeem in all forms of organisms, including humans, plant and bacteria. It is important to note that the liaison of CYP450 goes beyond drug metabolism just now it is excessively touch on in metabolism of xenobiotics, robust soluble vitamin and synthesis of steroids. With substratum specificity of more than 1000 and its ability to produce activated metabolites such as epoxide are the underlying reason for its dominance and grandness in drug discovery. The general appliance the CYP450 monooxygenase oxidization isR + O2 + NADPH + H+ ROH + H2O + NA DP+ ( anatomy 2)From the above formula it can be this reaction is of NADPH (Nicotinamide type A dinucleotide phosphate) and an oxygen molecule dependent. As menti unrivaledd above oxygen is important to increase the water solubility and in the same manner NADPH is in like manner important for oxygen activation and source of electron. excessively important for activation of oxygen is the presence of cystine amino paneling located near the protein terminal carboxyl of CYP450. Among the 500 amino pane of glassulent 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 assort as one of its ligand and it is the thiol which alerts the re occupation.Highlighting the numerous mediate structures snarled as well as range of iron, oxygen and proton (Figure) shows the catalytic conversion required for cp450 oxidation reaction to place. The bandaging of the subst ordination with low birle ferrous CYP450 enzyme induces a change in its active site. This testament effects the stability of the water ligand and de vocalism displace it (shown in the draw from a-b). Containing a high up spin heme iron the enzyme and substratum form a ferric complex. The change in electronic state impart result in the release and transfer of one electron from NADPH via electron transfer chain ( reduction ferric heme iron to ferric state) and thus reduction of the complex. The second electron is transferred when the complex reacts covalently with the oxygen forming a invigorated ternanry complex. Initially the complex is an unstable oxy-P450(diagram d), besides this is reduced to produce ferric peroxide by a loss of an electron. This intermediate is goldbrick lived and sustaines protonation twice resulting in a release one water molecule. Out of the oxygen molecules released one in incorporated in this water molecule and the rest into the substratum. Another method of form ing the iron-oxo intermediate is via the peroxide shunt which elimited steps from C to F.Some of the park addition of oxygen molecule reactions which CYP450 dependent are cognize 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 processedAromatic hydroxylation substrate generally 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 entrust ultimately give advance 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 man the electron donating will position it on t he 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 terminal figure 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, withal the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, specially 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, business relationship for roughly 50%. Metabolism of drugs given orally are greatly find by CYP450-3A primarily because this enzyme is present in both the liver and catgut and thus providing a barrie r for all drugs before they can enter the systemic circulations, otherwise ordinarily known as number one pass effect. Upon entranceway 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. This family of enzymes are also known to be cause of m either 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 mistakable to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major office staff in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also oxygen and NAPDH dependent, Flavin monooxygenases has much broader substrate speci ficity than CYP450. Once they have obtain associated with substrate the flavin monooxygenases is activated into 4-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 short as appropriate lipophilic substrate beats available it starts the process immediately. Adverse side effects are rarely associated with 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 4-hyroperoxyflavin. This is then followed by partition of per oxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4-hyroperoxyflavin has been regained apply NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times allow reduction back to its original parent form. intoxicant dehydrogenase and aldehyde dehydrogenaseThese families of enzymes are both zinc containing NAD specific and catalyze the reversible oxidation of alcoholic drink and aldehydes respectively. Grouped into 1-6 intoxicant dehydrogenase, are homodimer that exist in the soluble section of the tissue. It is involved in metabolism of some drugs such as cetirizine up to now 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 parcel of land for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulti ng in adverse side effects between alcohol and with certain analgesics drugs. alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a prospicienter half(prenominal) life and rapid absorption from the gut, methanol can result in series of displeasing side effects and metabolic acidosis, hence highlighting the immenseness of alcohol dehydrogenase. 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 highway of aldehyde or ketone back to its pharmacologically active alcohol form.Monoamine oxidase and diamineLocated in liver, intestine and kidney as some of its site, this membrane bound enzyme is divided into deuce classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deaminization t o 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 radical. The general mechanism for this enzyme is the two electron oxidation shown belowR.CH2.NH2 + O2 + H2O 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 all one molecule of oxygen is cloaked for every molecule of substrate oxidized (Principle of drug metabolism, 2007). Proportional to the rate of oxygen uptake this is unremarkably use to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenous substrates such as noradrenalin part monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their comm on 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 organic law of aldehyde from histamine and diamines in the same manner.ReductionThis passageway 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 excreta 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.HydrolysisAs 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 use uped as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and unwinder to be hydrolysed and will usually be eliminated unchanged at a high per centage 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 group esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are haughty 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 amalgamation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major brotherhood 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 gene linkage with adenosine triphosphate in presence of adenosine transferase enzyme. Itis this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group suffers attached to the sulfonium center marking electrophilic character (Principle of drug metabolism, 2007). Depending on the available group present on the substrate Conjugation via methylation is broken down to nitrogen, oxygen and sulfate methylation.O-methylationO-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme obligated for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, foun d 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 bigger it is the slower the rate of reaction degree of acidity of the catechol group itself.N-methylationNaturally 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 monumental 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 thesereactions 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) quite a than an exchange process.Sulfate and phosphate labor unionSulphate uniting is one of the most important reactions in biotransformation of s teroids, 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. slackly 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 organize 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 (pr oducts are stable arly sulfate esters with a high affinity). Substrates are generally of mediocre 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 head teachering 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 u rine. This pathway is important due to the fact there is a high availability of glucucronic acid, huge substrate specificity and the large-minded 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 configuration. However products produced are in -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) such 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 i n the ER uridine-5-diphosphae-alpha-D glucoronic acid is produced due to oxidation of carbon position six of UDP--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 compartmentalisation 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.AcetylationInvolving 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-a minosalicly. 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 tercet to build of unconjugated compounds in the blood and hence leading to toxicity.Conjugation with co-enzyme ACommonly using this pathway are the carboxylic containing which are activated into an negociate 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 t o cause problems with this pathway is the occurrence of toxicity, rare but serious as it the conjugates interject with normal endogenous pathway. A common example was seen with NSAID which have now been long removed from market.Conjugation with amino acidThis 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 GlutathioneConjugation 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 run an important role apart from catalysing as upon binding of the active side with the glutathione will results in 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 n ucleophilic 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 liverWhen 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 circumstance 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, f or 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 ( plot 2), with the intermediate being DM-naproxen. Usually conjuga tion 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 grou p, 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 helper 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-solu ble 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 NaproxenNaproxen is a widely prescribed NSAID and works extraordinarily well however there are several hateful 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 hydrogeProcesses of Drugs Metabolism in the BodyProcesses of Drugs Metabolism in the BodyAbstractMetabolism 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 e xcretion 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, po lymorphism can also cause idiosyncracity of certain drugs to be toxic.1.1 Phase IPhase 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 OxidationAccounting 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 isR + O2 + NADPH + H+ 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 protonation 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 processedAromatic hydroxylation substrate mostly produces phenols such as that seen on figure 3. The production of Phenol can be either via a non enzymatic rear rangement 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 ha nd 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. This 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 monooxy genasesSimilar 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 4-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 associat ed with 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 4-hyroperoxyflavin. This is then followed by cleavage of peroxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4-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 dehydrogenaseThese 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 dehydrogenase. 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 diamineLocated in liver, intestine and kidney a s 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 belowR.CH2.NH2 + O2 + H2O 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 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.ReductionThis 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 lipophili city 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.HydrolysisAs 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 a s 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. Itis this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group becomes attached to the sulfonium center marking 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-methylationO-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocat echol 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-methylationNaturally 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 am ine 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 thesereactions 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 produ ct (fig 7b) rather than an exchange process.Sulfate and phosphate conjugationSulphate 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 configuration. However products produced are in -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) such a morphine. The transformation of th e 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--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.AcetylationInvolving 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 ACommonly 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 acidThis 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 GlutathioneConjugation 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 in 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 protectiv e 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 liverWhen 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 kn own 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 m etabolite 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 invo lved 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 NaproxenNaproxen 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

History of Fireworks :: Chine Fireworks Explosives Essays

History of FireworksThe birthplace of fireworks is generally recognized as China, with the low gear explosive mixture found being black powder, during the Sung dynasty ( 960-1279 ). It is said that a cook in ancient china found that a mixture of sulfur, saltpeter, and charcoal was very flammable and would explode if enclosed in a small space. The first application of this technology was for entertainment. The Chinese are still the leader in the production of fireworks. Once the recipe for black powder was perfected, they found that it was easily used as rocket fuel, and they made hand carved wooden rockets in the shape of a dragon, in the sixth century. These rockets shot rocket powe blushful arrows from their mouth, and were used against the Mongol invaders of 1279. The principle behind these rockets is still used in rocket powered fireworks today. Through adventurous explorers, the knowledge of making fireworks spread west, through Arabia in the seventh century. The Arabs called the rockets Chinese arrows. The Mongols are credited with taking Chinese rockets and gunpowder to europium around 1241. The first record of their use in Europe are around 1258. Until the 19th century, fireworks lacked a major aesthetically of the essence(p) characteristic color. Pyrotechnicians began to use a combination of potassium chlorate and various metallic salts to make brilliant colors. The salts of these metals produce the different colors strontium burns red copper makes blue barium glows green and sodium, yellow. Magnesium, aluminum, and titanium were found to give off white sparkles or a flash. Even though China invented the fireworks, Europe surpassed them in pyrotechnic development in the 14th century, which coincides with the time the gun was invented. Shot and gunpowder for military use was made by skilled tradesmen, later on called firemakers, who also made fireworks for peace or victory celebrations. During the Renaissance, two European civilises of pyrotechni c thought emerged one in Italy and the other at Nuremberg, Germany. The Italian school of pyrotechnics emphasized elaborate fireworks, and the German school stressed scientific advancement. Both schools added significantly to further development of pyrotechnics, and by the mid-17th century fireworks were used for entertainment on an unprecedented scale in Europe, being popular even at resorts and public gardens. In the mid-19th century fireworks became popular in the United States. Injuries associated with fireworks, curiously to children, eventually discouraged their unrestricted use. As a result, in many states of the U.

Experimental Psy Article Review :: essays research papers

Experimental PsychologyArticle review of Distorted Retrospective Eyewitness Reports as Functions of Feedback and Delay by Gary L. Wells, Elizabeth A. Olson, and Steve D. Charman.Iowa State University daybook of Experimental PsychologyThis article was mainly about eye witnesses and the many errors they make in recalling a situation or describing a perpetrator whether they ar asked warmly or after a period of time.In this study, witnesses viewed a crime video and attempted to identify the culprit from a group line-up that did not actually have the culprit present. 253 mistaken- denomination eyewitnesses were randomly given confirming, disconfirming, or no feedback regarding their description of the culprit or the culprits identification. The feedback process was either immediate or delayed for 48 hours, and measures were also immediate or delayed for 48 hours. It was shown that those who were given confirming feedback gave more distorted information. They had increased confidence in remembering what had happened, were able to make out facial details and their length of time to identify the culprit changed. There was also no difference in their statements when they were asked immediately or after 48 hours. Those who received disconfirming feedback were not so confident and took longer time to identify the culprit.The writers argue that the focus on identification itself, especially in court cases, does not factor in the influence that postidentification suggestions have on the testimony of the eyewitness that might later be given about the identification. They suggest that postidentification feedback from the lineup administrator has strong effects on how the eye witness remembers the original event and on how the eyewitness recalls the identification decision. They call this the Postidentification Feedback Effect. This Effect influences both the retrospective reports of confidence and the eyewitnesses retrospective reports of how good their view of the culprit was, how much attention they paid to the culprit, how long they took to identify the culprit and so on. According to the writers, any psychological interpretations of the postidentification feedback effect must take into account the broad range of effects on retrospective reports of the witnessingexperience quite than merely the effect on retrospective confidence.There have also been recent studies that have replicated and extended the Postidentification Feedback Effect in various ways. According to bingle study, the Postidentification Feedback Effect is reduced by having eyewitnesses think privately about their certainty, the view they had, and so on, prior to giving them feedback (Wells & Bradfield, 1999).