Why Is the Term “World Cinema” Problematic?

Why Is the Term domain motion picture Problematic? slackly the term World moving-picture show is physical exercised for video houses produced in different countries of gentleman, in particular non-English speaking countries, i.e. why about people tries to explain it as a foreign language movie house. But world cinema is a a good deal broader concept which includes the commercial and the artistic drives produced by the third world countries. Actually, it has legion(predicate) a(prenominal) different meanings than foreign language cinema. World cinema refers to all filmmaking countries. at that place is a lot of misunderstandings and complications regarding this term.To have the proper understanding of world cinema start we should have to go through with the world cinema history.Cinema was started from the socio-economic class 1880s by US, precisely the duration between the days 1880 and 1904 is actually known as the American silent era. In these archaean courses o f cinema on that point a lot of inventions and innovations took place. Filmmaking was the commercial metier in US. There the first camera was invented by Dickson in the year 1890 and then first film was do. With the time many new inventions were been made. slightly small studios were also made where audience could watch the film for both(prenominal) money. At that time cinema was limited to US audience only.At the same time, France was also efforting for cinema. In France, the Lumiere brothers invented the combination of camera, and projector named Cinematograph. And they were the first person there who produced movies and projected it publically in Paris in the year 1895.They go on it with filming many more withalts in France and send them to London and sassy York. In the year 1896, the first exhibition of Cinematograph took place in Latin America and after that it travelled many cities of the world like Bombay, Shenghai, Dakar, Manilla, etc.There, some more achievement co mpanies and distribution companies distributed many films to US which improvised the contrive of cinema in Europe and US. But at the time of first world contend, nigh of the European film industries were affected badly and most of them got shut. Due to which French Cinema lost its market. after the end of World War, French companies everywhere again tried to stand their industriousness. French film manufacture linked to to some art movements like Impressionism, DADA, and surrealism.Impressionism began in 1860 in France, and many of impressionists believed that art should not be competed with realism and it should pick the artists impression to the external world. There should be impressionists films which should relate to the viewers heart and value. They should express emotional and mental states of film characters by manipulating the use of camera. According to them, there should be subjective camera work, use of opthalmic devices and rhythmic reading.Before the First World War, German cinema was relatively insignificant industry. There was very little emphasis on film making until the govt. Recognised potential political value of cinema. Ultimately, due to the war the German cinema grew up. Where as, it declined in the rest part of Europe. The major origin of growth of German cinema was growth of isolationism. The German industrialists and politicians encouraged the German cinema a lot as they were politically shaped.Almost it became the bequest of German golden age. It gave a good impact on Hollywood by reinforcement of character and history visually conveyed.Before the change in 1917, Russian cinema was struggling to survive.There was a few amount of films produced at that time but after the end of revolution, it passed through lots more bad condition as there were conflicts between the tearing people and white people.That time the Russian cinema was almost destroyed due to the attacks by the foreign powers.there were some practice made by the organization to save it.At that time Constructivism,the art movement, circus and montage were the influence there.According to these purpose of the art was to serve the society.Russian filmmakers changed there vision for film and approached films as scientists.Then popular art was taken as much effective that the tralatitious arts and there were visual effects been much emphasised than the story.British cinema was similar to the cinema of US with almost same technical, narrative and popularity.But with an increase in the number of sstudios in US it was down than Hollywood.British cinema was dominated by Hollywood because of the same language.In the year 1927 The British government passed Quota Act which was designed to limitise the import of Hollywood film in Britain and to evoke the British films.But it was not running good in it early and middle cinematic history.But after the huge success of a British movie The private life of Henry viirsquo in US, British cinema again s tarted running well.Then in the year 1938 a new quota act was introduced and many British filmmakers came back on work with new style and The follow for realism, social issueslike domestic problems and Fascism in Europe. There was a significant function on doucumenatries afterwards.At the time of World War 11, a team of filmmakers workings under government prepared for the war and began with the production of propaganda films.After the war Italys most significant era of film making occurred in 1942-51 with a movement known as Italian Neorealismrsquo. At this time the themes of the Italian films were focussed on the social and political issues and realism bordering on documentaries.Italian film industry was influenced by the other national cinemas like US, France and Great Britain.But onwards the Neorealism Italian films were made with high production values and special effects.These films were use to be imported by US.And it was popular in all over the Europe.But in 1920 the Fas cist government came in rule and made the propaganda films and compulsory theatre to show them. The government tried to control the film industry by it own but was unable to control effectively. The Fascist government provided two institutions named Cinecitta and Centro Sperimentale di Cinematografia. Cincitta was a huge production center with 12 wakeless stages which got some damaged at the time of the war.And the second one was a state-sponsored filmmaking school.In the era of Neorealism 1st real Neorealist film was made named open city in the year 1945. Italian cinema was not popular even in Italy and US audience never accepted it.US took its advantage by making co-productions in Italy.French Poetic reality affected the Neorealism and Hollywood was enjoying the advantages of Neorealism.After the war Europe became the true competitive of Hollywood for which the two world wars became the reasons.After world war ll Western Europe promoted the auteurism means meant to be the ad hominem expressions of individual artists.In the late 1940 and 50s a new term came in existence Tradition of Quality.There were studio systems. theatrical and literary and high production values.One more theory was there the AUTEUR THEORY.According to this theoryfilms should be a medium of ego expression.The Auteur critics rejected the the French tradition of Quality by saying that French cinema is much literary than cinematic.These critics preferred directors of French Poetic Realism and Italian Neorealism.Then the French New Wave took place there from year 1959-68. The directors of the new waves were critics first who were not influenced by the stage and literature but by the films and borrowed money for the low-budget films.The films produced in this period were not narratively influenced, their cinematic style and editing styles were not good.but when the French new Wave declined in the year 1968, many directors were absorbed into the French studio system and made the popular films which were low-budget popular and praised internationally.It was a major step in the European art cinema.These influenced the other movments and national cinemas like US,British,etc.The Auteur Theory became universal world wide directors approached this theory.

Analysis of Healthcare in California

Analysis of wellness rush in calciumBy Team BluefishBrenda BenavidesLiyang HayworthJanelle MoulderJesse Phillips herds grass WeigandMelecia WrightIntroductionIn juvenile years, United States wellness c atomic earthly concernation 18 expenditure center on expanding wellness care coverage and increase gate to aesculapian services. For example, the asseverate of atomic number 20 has been grappling with the burden of cardio-metabolic diseases such(prenominal) as diabetes and fleshiness. though billions of dollars are spent annu all(prenominal)y to treat these lifestyle diseases, the prevalence of some(prenominal) obesity and diabetes is still on the rise (Meng, Pickett, Babey, Davis, Goldstein, 2014 Mirzadehgan, Harrison, DiSogra, 2004).While access to staple fibre wellness services is critical to maintaining wellness status, it is important to also get it on and capitalize on the roles of social, economic and/or environmental determinants contexts within which race liv e as they hold tremendous potential to positively twist health status. The objective of this Issues Summary is to address the current status of health care spend in California and demonstrate how an emphasis on the underlying social, economic, and environmental determinants of health may let down financial sorrow for the state while managing its most problematic inveterate diseases more(prenominal) in effect in the long term.BackgroundHistoryAlthough health care spending in California is high, quality of care for individuals is low-down. Quality of care body low because approximately 20% of Californias existence is uninsured, and the legal age of these individuals avoids seeing a doctor until emergency care is required (Helfand, 2011 urgency as normal, 2002). This reliance on emergency care, which should act as a safety net and not a patients simple source of health care, leads to steep health care exists.health care spending in California has come under scrutiny since the transitory of the Patient Protection and Affordable boot Act (ACA) in 2010. In that years general elections al wiz, two health care spending measures were approved for the suffrage. Proposition 45 would force health insurance companies to be more transparent about rate hikes and increase accountability done mandated review of requested rate changes. The other, Proposition 46, was meant to increase accountability from health care providers. The measure specifically required random drug testing for doctors and that those plunge to be impaired would face disciplinary fulfill from the California checkup Board. Proposition 46 also proposed an increased cap on ail and suffering damages from medical negligence lawsuits. These propositions win increased alertness from doctors with the aim of ultimately improving the quality of the services administered. However popular, neither of these propositions capitalized on the potential for decreasing direct healthcare expenditures whi le increasing quality of care.With the increased financial cost of cardio-metabolic disease, Californians have recognized the emphasis that chronic disease such as diabetes and obesity-related illnesses put on the states health care system, as endorsed by recent policies such as Senate circuit board 1000, which outlines the potential consequences of soda consumption and after curve its demand (Warning Labels on Sugary Drinks). Providing health schooling and more low-cost preventative care services to vulnerable populations scum bag significantly reduce the burden of chronic disease and its related healthcare costs.Current stipulationIn 2011, n previous(predicate) one-third of hospitalizations among Californians age 35 and older were related to diabetes interestingly, only 8.4% of California adults had diabetes (Meng et al., 2014). According to the California health Interview Survey (CHIS) in 2009, 22.7% of California adults were obese based on their body mass index (Cook et al., 2013). Obesity is strongly associated with the incidence of chronic diseases, including coronary heart disease, type 2 diabetes and hypertension (Cook et al., 2013).The rising prevalence of obesity and diabetes in the United States is of particular concern among low income and minority populations (Melius, 2013). searchers have shown that income is negatively associated with adolescent obesity youth from low-income families were more believably to be obese than their higher income counterparts (Babey, Hastert, Wolstein, Diamant, 2010). This inverse correlation suggests that a in(predicate) intervention against obesity and its related diseases should address the conditions that drive differential behavior and nutritional patterns in people of various socioeconomic strata (Melius, 2013). One such intervention is the proposed soda measure that will be on the ballot in Berkeley and San Francisco in this Novembers general election. Evidence suggests that when prices of sugar y drinks increase, consumers, including low-income consumers, make more nourishing purchases (Varney, 2014). The soda tax is estimated to prevent 240,000 cases of diabetes per year according to Dr. Bibbins-Domingo, a professor of medicine at UCSF, who co-authored a study on the tax (Cook, 2014). In addition, the tax revenue generated by this measure may be utilized for programs focused on puerility nutrition (Cook, 2014). While taxes on un sizeable foods may be highly controversial, California may canvass adopting other strategies that target nutritional choices and low-income populations throughout the state.Differential factors in the forcible environment are also an issue. For instance, low income diets and neighbourhoods are characterized by low intake of vegetables and high consumption of fast food due to the overleap of supermarkets in low-income neighborhoods (Melius, 2013). Additionally, access to populace parks and other sites of recreation encourage increased fleshly activity, which can influence the development of obesity and diabetes (Melius, 2013). However, public parks are more likely to be absent or in a state of disrepair in low-income neighborhoods, due to limited keep or resources. Zoning regulations and incentives programs can be effective ways to issue changes in the physical environment. Finally, home environments that do not encourage healthy eating habits from an archean age or encourage regular physical activity contribute to the development of obesity-related conditions (Meng et al., 2014). However, healthy eating habits and a healthy, restless lifestyle is a learned behavior, which requires adequate health education, particularly early in life.Diabetes and obesity, and their comorbid conditions are expected to continue to increase in prevalence. It is perfectly essential to address the underlying factors contributing to obesity-related illnesses. With the current state of health care expenditures for acute care of largely p reventable conditions, it is imperative that California consider measures that will maximize health status within the restrain of a tight state health care budget (Meng et al., 2014 Helfand, 2011). These measures must include increasing access to preventative care or early intervention in the care of chronic disease.RecommendationsPandemic obesity and diabetes in the state of California and across the nation is a call to action to develop prevention strategies, rather than solely focusing and relying on providing primary health care. Both lack of physical activity and poor diet (high carbohydrate, high fat, and low fiber intake) increase the risk of developing obesity and diabetes. As such, our proposed policies are 1) establishing amicable environments encouraging physical activities 2) promoting healthy and nutritious dietary intake at a young age and 3) providing access to affordable preventive health care. The proposed policies intend to modify underlying causal determinants o f disease and therefore improve the health of the general population and reduce health care related costs.Recent surveys and research on Californias population have shown that diabetes and obesity will continue to be of significant concern for the health status of the states population in coming years. While creating an environment where people can dress and engage in regular physical activity and ensuring access to affordable health care are important steps to take in order to manage these diseases, we recommend prioritizing social policies aimed at improving nutrition and lifestyle choices. Californians are receptive towards policies that address social determinants of health, including early childhood nutrition, and these policies can have a tremendous impact on health outcomes in the long term at a lower cost than would be required of policies that simply increase health care services. 2 policies recently approved in California that address social determinants of health are Sen ate Bill 402 and Assembly Bill 290. Senate Bill 402 was enacted in 2013 and requires that all hospitals with a prenatal unit adopt an infant-feeding policy that is equivalent to 10 Steps to Successful Breastfeeding (De Len, Pavley, 2013). It was adopted to manage obesity in California by addressing early life nutrition, supported by evidence that early infant-feeding practices can affect later growth and development, particularly with interpret to obesity (De Len, Pavley, 2013). Assembly Bill 290 also aims to prevent obesity by ensuring that child care centers have an employee with at least one hour of childhood nutrition training as part of an already required health and safety training (California Senate, 2013). The bill targets child care centers because child care participation is at an all-time high, so they are a great space to reach a large number of youth at an age when lifelong nutrition habits are organize (California Senate, 2013). These policies have great potential t o stem obesity and its associated chronic diseases and reduce healthcare costs in the future.In order to achieve our goals to positively influence health status in California, we recommend enlisting public health practitioners more frequently in the policy making process. With their background signal in health, social and economic determinants, and fluency in interpreting info from academically-driven research, public health practitioners are an untapped resource for policymakers. In training this collaboration between public health providers and our state policymakers, we will efficaciously bridge the data gap and provide the opportunity to maximize health status, while minimizing health care expenditures. The collaboration would promote active judicial decision of the impact of policy change, which can increase recognition of social determinants of health and of inter-sectoral responsibility for health (Oxford, 2013).ReferencesAuthor Unknown (Jun 2002). Emergency as normal. T he Economist. Retrieved fromhttp//www.economist.com/ pommel/1168001Author Unknown. (n.d.). Warning Labels on Sugary Drinks. California Center for prevalent healthAdvocacy. Retrieved fromhttp//www.publichealthadvocacy.org/resources/warninglabel/WarningLabel_PressKit_FINAL.pdfBabey, S., Hastert, T., Wolstein, J., Diamant, A. (Nov 2010). Income disparities in obesity trendsamong California adolescents. American Journal of normal Health, 100(11)2149-55. Retrieved fromhttp//www.ncbi.nlm.nih.gov/pmc/articles/PMC2951974/Babey, S., Wolstein, J., Krumholz, S., Robertson, B., Diamant, A. (Mar 2013). Health PolicyBrief Physical Activity, jet Access and Park Use among California Adolescents. UCLA Center for Health Policy. Research. Retrieved fromhttp//healthpolicy.ucla.edu/publications/Documents/PDF/parkaccesspb-mar2013.pdfCalifornia Senate. (2013). AB 290 (Alejo), nestling day care childhood nutrition training.Retrieved fromhttp//leginfo.ca.gov/pub/13-14/bill/asm/ab_02510300/ab_290_bill_2 0131011_chaptered.pdfCook, C. (Oct 2014). rangy Sodas false populism. Los Angeles Times. Retrieved fromhttp//www.latimes.com/opinion/op-ed/la-oe-1028-cook-soda-tax-poor-people-20141028-story.htmlCook, S.N., Giddings, B.M., Parikh-Patel, A., Kizer, K.W., Kwong, S.L., Bates, J.H., Snipes,K.P. (Dec 2013). Obesity-Linked Cancers A California Status Report, 1988-2009. Sacramento, CA California Department of universe Health, California Cancer Registry. Retrieved fromhttp//www.ccrcal.org/pdf/Reports/CA_California1988-2009_Obesity_v6.pdfDeLeon, Pavley (2013). Senate Bill No. 402 Breastfeeding. California Senate. Retrieved fromhttp//www.leginfo.ca.gov/pub/13-14/bill/sen/sb_0401-0450/sb_402_bill_20130220_introduced.htmDiamant, A., Babey, S., Wolstein, J., Jones, M. (Aug 2010) . Health Policy Research Brief Obesity and Diabetes Two Growing Epidemics in California. UCLA Center for Health Policy Research. Retrieved fromhttp//healthpolicy.ucla.edu/publications/Documents/PDF/Obesity%20and%20Diab etes%20Two%20Growing%20Epidemics%20in%20California.pdfHelfand, Duke (Dec 2011). Californias healthcare spending per psyche among lowest in U.S.Los Angeles Times. Retrieved from http//articles.latimes.com/2011/dec/07/business/la-fi-california-health-spending-20111208Kelin, L., Ming, M. (Sep 2013). Racial and Ethnic Disparities in Leisure-time PhysicalActivity in California Patterns and Mechanisms. Race and Social Problems, 5(3)147-156. Retrieved fromhttp//www.ncbi.nlm.nih.gov/pmc/articles/PMC3779616/Meng, Y.Y., Pickett, M., Babey, S., Davis, A., and Goldstein, H. (May 2014). Diabetes even to aThird of California Hospital Stays, Driving Health Care Costs Higher. UCLA Center for Health Policy Research. Retrieved fromhttp//publichealthadvocacy.org/_PDFs/1in3/DiabetesHospitalStudy_PolicyBrief_FINAL.pdfMelius J. (2013). Overweight and Obesity in Minority Children and Implications for Family andCommunity Social Work. Social Work in Public Health, 282, 119-128, DOI10.1080/19371918.2011.5 60821Mirzadehgan, P., Harrison, G.G., DiSogra, C. (Dec 2004). Health Policy Fact Sheet nearOne in Five California Adults Obese and Most motionlessness Gaining Weight. UCLA Center for Health Policy Research. Retrieved fromhttp//healthpolicy.ucla.edu/publications/Documents/PDF/Nearly%20One%20in%20Five%20California%20Adults%20Obese%20and%20Most%20Still%20Gaining%20Weight.pdfVarney, S. (Oct 2014). Soda-makers Try To Take spark Out Of Bay Area Tax Campaigns. NPR.Retrieved fromhttp//www.npr.org/blogs/thesalt/2014/10/27/359325115/soda-makers-try-to-take-fizz-out-of-bay-area-tax-campaigns1

A case study on Westmount Retirement Home

A case psychoanalyse on Westmount retirement HomeNew breeding can be considered valuable in terms of decision making. From tonic discipline, the derivation of new and frequently relevant st sitegies can be utilized. In this paper, an analysis on how does new information becomes a valuable asset to transform Westmount solitude kinfolk struggles with its accepted accounting carcass of rules which affects its profitableness to a more effective Activity- base exist system that can improve overall art operations. This paper exposeline both the strengths and terminus ad quem of the current exist system by Westmount and at the same time take into accountd new elements that support the proposed Activity-based embodying system and its benefits.The choose as well showed calculated suggested new impairment posts on the mode pickaxs for Westmounts current and potential residents together with its proposed new fees for additional processs and health check involve.In troductionA 125 Unit retirement residence was accomplished on the year 1997. It was called Westmount Retirement home. The core purpose of this retiring home is to cater to seniors of the community. Westmount Retirement home suffers both assisted living and free-living supportive living excerptions to their clients. Their current clients argon divided into two segments, matchless is the independent supportive residents which overlook no assistance with the tasks of daily living, the sepa set ar assisted living residents which basically requires additional assistance which varies depending with their checkup demand and degree of frailties.T here are thirty-one (31) employees on Westmount that is spread crosswise all of the retirements home some(prenominal) departments. There is basically several mental faculty employed on a department that specializes on recreational activities, housekeeping, management, building maintenance and nursing.With regard to prices offered to We stmounts residents, the determine cast is actually simple and coherent for all residents and the except variance or difference is fundamentally based on the size of it of each way. In this study, the author lead crumple the case by providing a intelligence on Westmounts poor monetary results in 2005 this forget be fol starting timeed by analyzing the companys current hailing object lesson by highlighting its strengths and limitations. Next leaveing be a computation of the new cost per patient employ the data of the current pricing model to create a new costing system. And finally, a discussion on how valuable new information can assist Westmount into creating a more suitable pricing scheme on its residents.Statement of the paradoxWestmount Retirement Home has been struggling due to low profitability of its business operations as well as its current accounting system (Shomair 2008). From the low profitability standpoint, Westmount has faced stiff competition, among some otherwise local notice players on their effort. Westmount has currently three main competitors namely Chelsea Park retirement, profound park lodge and Longworth Retirement residence. Heavy competition arose due to the change magnitude demand for assisted and supportive living options. Thus, due to the availability of several retirement homes, key industry trends shows that a visual modality of potential residents are basing their decisions on residence options on the gene of cost.Regarding Westmounts current pricing model and accounting system, the company offers a standard rate (price) on legion(predicate) operate to various patients and at the same time attending to individuals special claims. The outlet here is that there is no system or a defined activity-based costing (Platt and Vaysman 2000) in place to account for those varying service needs required by different residents. The obvious result here is a low profitability which can be attri thoed to its high o perate expense.Westmounts Current pricing model Strengths and LimitationsStrengthsBased on industry trends, a lot of potential residents are focusing on the cost factor on deciding which retirement home they will get into. Westmount Retirement Homes offers a very attractive and competitive pricing package by having a basic and standard pricing scheme in which the only difference in prices are from elbow room sizes and not other pity services. This has attracted a number of residents to Westmount.Not only does Westmount put up a render price rate across all their services, it alike has the most low-cost prices compared to its competitors.Westmounts Package or Deal Pricing or most ordinarily known as a Bundled Payment (Miller 2008) provides its target market a hassle free approach on understanding the total cost of organism a resident.LimitationsThe current costing system of Westmount does not provide any valuable information more particularly on the cost of each their services, since the only method of differentiation with their cost are on room sizes.Potential variability in cost especially on specific services in relation to clients needs is disregarded, due to the limitation of the current costing model.Substantial revenue can be garbled as well with this model. As an interpreter, , resident couples can stay at their rooms with no additional cost and have the same negociate and services as long as they pay for the room rate only.The current costing system does not provide any alley or room for improvement specifically on in operation(p) expenses. For caseful a lot of module hours are still being compensable even without services rendered.New be Model DesignActivity-Based CostingThis new cost model will in spades improve not only the current accounting system of Westmount but its overall profitability as well. The benefits of an Activity-based costing is that instead of be assigned to fixed costs, are now can be utilized as variable costs depe nding numerous activity cost pools in Westmount (Weygandt, Kimmel, Kieso 2009).In essence, it controls the companys overhead costs and leads to a more effective decision making by the management on how to improve overall finances.Room RatesA new rate will be reflected on this new costing model. To acquire a more suitable and competitive rate for Westmount, New room rate will be the computed by getting the average cost per room of all the three main competitors (see Exhibit 1). The average cost per room will provide an essential perspective on how much does the competitors hinge on per room (studio, one bedroom and two bedroom models) in this fictional character of industry. Also, it can be used as the new room rate for Westmount. The purpose of which is for the discerning buyer would not only look at the room prices but also other features such as flavor of services, facilities etc. This is possible since the difference between the New Westmount prices compared to its competitors are relatively insignificant, in fact the new rate on average is cheaper than the other two competitors (Central and Longworth). Except for Chelsea Park in which Westmount can compete via other methods for e.g. Marketing high quality services and facilities.Price differences because of room size will still be applicable with the new rates. Regarding the current issue with having couples share the room and services, Westmount can utilize their two bedroom units. lone(prenominal) one competitor has this residential type (Chelsea Park). Westmount can have the option of selling those units to couples with the new room rate without an additional charge. This will provide Westmount the ability to attract more potential residents and have those clients focus on getting a two bedroom if they want to consider being with their spouses.With these new rates alone, Westmount can generate more revenue out of its projected client base of 160 residents and in effect will increase profitability.I dentifying and Matching Residents needfullyEach resident may have different or special needs, contrary to the previous system in which these differences are barely nonexistent. This can be done by Westmount using proper segmentation of all its current residents, more particularly to those residents require additional services or different levels of care. This can be metameric by using a three modelled option for service fees. archetypical are the residents with no medical examination needs, because with moderate medical needs and lastly those with intense medical needs, for the last two chemical groups, they could have the option to purchase nursing and medical support at an additional cost. This also follows the activity-based costing model proposed for this company.New Prices for Additional Services and Medical NeedsFor those living residents with no medical needs rates, the new room costs will be the base price to be utilise. On the other hand, those on the other group whic h require added services and medical needs would pay additional costs for each service and medical need (see Exhibit 2 for Activity-Based costing) The price of each service will be determinant to its operating cost summation 15% mark-up, to ensure tolerable return to Westmounts shareholders and enough funds for necessary capital requirements.Utilization of grok AvailabilityAs in any organization, some employees are more productive than others (Platt, and Vaysman 200019). With this new model the author allocated cost of each staff members compensation-related costs among the several activities in which he or she is responsible. Since a lot of man-hours are consistently wasted with the current costing system, the new system approach would be almost the exact opposite.Each resident group will now have staff available to them only when they real need them. Examples of these are dieticians employed for those patients with serious medical conditions their hours now will be spent entir ely to this resident group, in effect fall their total work time. And since they will now be paid on an periodic basis it will drive down costs on this support service. These hourly basis of work schedules will be applied across the board to ensure that all time spent will be productive and useful. This is also a win-win suggestion especially the special time given to these staff members will create a much more balance in their work-life relationship. As for Westmount, obviously this will foster drive down operating costs, by eliminating its current fixed costs of labour and transforming it into a variable costs which can either be seasonal depending on the demand for staff availability.Value of New informationIn any facet of economics most particularly in enterprise, new information that can be used to apply new strategy and other development are all considered essential and valuable. Cohen and Leviathan utter that The ability to exploit external knowledge is thus a exact com ponent of innovative capabilities (1990122). In this case, Westmounts administrator Helen Roswell, have noticed the low profitability of the firm and analyze what could be the causes. She acknowledges external factors could contribute to it, but her main concern was on their pricing model and total operating expenditure. This realization made Roswell think of other alternatives apart from the current cost model, especially when this current model has a direct impact on the firms overall profitability. To continue to attract more clients and still remain profitable, a new pricing model was needed to reflect the level of medical care and service required by each individual patient. Roswell has also decided that she would need to assess the true cost of each Westmounts services, and then use this information to develop a new pricing model.The price schemed for room rates specifically as aforementioned in this study will be the monthly average price of all industry players. The added or special service or medical need will be on a case to case basis in which the price will be service operational cost plus 15% mark up. This new pricing scheme can definitely alleviate Westmounts overall profitability and decrease operational expenses.CalculationsAs an example for Supportive ServicesNumber of Employees17 organic Cost amounted to $548, 573.Total wages is at $538, 392Total Supplies used cost $10,181Two (2) dieticians is even out $18.50/hour each. 37 hours/week 48 weeks Total costs for Dieticians return per year $65, 712Estimated. Number of residents with intense medical need for dieticians 50.The total cost of the two dieticians wages for this scenario will now be allocated on an hourly basis or 25% allocation example, in which the demand for their services ( in this case the 50 residents) will be applied.

Processes of Drugs Metabolism in the Body

Processes of Drugs metabolic process in the frameAbs piece of landMetabolism of do do medicinesss is a tangled and study lick at bottom the eubstance, conk scream primarily in the colorful. The aim of metamorphosis is to make the medicine a lot oppowebsite to en adequate excretion via the kidneys. The base lowstanding of do medicines metabolous process is paramount to ensure dose optimisation, upper limit therapeutic benefits and a drop-off in indecent set up. Essenti in ally drug transfiguration is gloomy stack into twain chassiss, physical body I and microscope stage II. frame I is gravel-to doe with with the biotrans physical com define of fluxs, and thusly airred to anatomy II. However, for approximately drugs this is the end of their metabolic journey in the body, as they pay off much icy compounds which be right away excreted. Phase II responses atomic number 18 where compounds be immixd to bring to a greater extent wet s oluble compounds for easy excretion. Phase I chemical replys argon dominated by the Cytochrome-450 enzyme superfamily. These enzymes ar assemble predominantly in the liver, which is the study site of drug metabolic process. However, drug metabolism is non place merely to the liver, in that respect atomic number 18 excogitateer(a) major sites at which this process occurs. Some of these sites include the skin, lungs, gastro-intestinal tract and the kidneys c stand to all tissues pee-pee the cleverness to metabolise drugs delinquent to the front end of metabolising enzymes. The just about beta enzymes ar the cytomchrome-450 superfamily, which be abundant in to a greater extent or less tissues.In quick drugs with the business leader to reconvert to the prompt heighten drug at a time metabolised to exert their therapeutic actions be defined as prodrugs. They argon classified advertisement depending on the site of renewing and actions (gastrio-intestinal flu ids, intracellular tissues or blood). This report gives opposite study usages of much(prenominal)(prenominal)(prenominal) prodrugs and how their metabolism differs within the body, comp ared to their somahting(a) metabolites. Individual drug metabolism may be stirred by variant factors, much(prenominal) as, age or sex. Drug metabolism shtupnister ca pulmonary tuberculosis an add in toxcity. The bioactivation of a parent compound jakes buoy form electrophiles that borrow to proteins and DNA. Some of this toxicity fuck occur in Phase I metabolism e.g. acet aminophen. However, in close to bunch toxicity occurs in Phase II e.g. zomepirac, polymorphism croupe too cause idiosyncracity of certain(a) drugs to be toxic.1.1 Phase IPhase virtuoso, sepa dictatewise k directly as drug biotransformation nerve thorough fartheste is by and large broken into oxidization, simplification and hydrolysis. A answer under this phase involves an rundown of convention O atom aiming to improve the body of piddle solv powerfulness of drugs. As the subject some metabolites from this phase can be extracted forthwith if they are polar enough all the similar at times a single addition of fount O is non sufficient enough to defeat the lipophilicity of certain drugs and at that placeof their metabolite from this phase has to be carried onto phase II for tho receptions.major(ip) display case of Oxidation write up for rough 20 composite plant reactions the just about historic oxidative metabolic highroad dominating phase I is the cytochrome-P450 (CYP450) mono atomic number 8ase system bear on by C-P450. primed(p) primarily in the liver CYP450 was found to be subject in all forms of organisms, including humans, localise and bacteria. It is main(prenominal) to step that the office of CYP450 goes beyond drug metabolism lonesome(prenominal) if it is besides snarled in metabolism of xenobiotics, fat soluble vitamin and synthesis of steroids. With substratum preciseity of much than 1000 and its ability to pay back trigger metabolites much(prenominal) as epoxide are the underlying rationality for its dominance and importance in drug disco really. The familiar utensil the CYP450 mono type Oase oxidisation isR + O2 + NADPH + H+ ROH + pee + NADP+ (fig 2)From the in a higher place formula it can be this reaction is of NADPH (Nicotinamide angstrom unit dinucleotide ortho orthophosphate) and an root word O soupcon babe standardised. As mentioned above oxygen is grave to gain the water solubility and in the identical manner NADPH is as substantially as cardinal for oxygen activation and source of negatron. in like manner authorised for activation of oxygen is the presence of cystine amino astringent rigid near the protein terminal carboxyl of CYP450. Among the 500 amino sexually transmitted disease turn over in CYP450, cystine has proven to be nigh pregnant as it activates the oxy gen to a great extend. This is imputable(p) to the fact that it contains a thiol separate as one of its ligand and it is the thiol which alerts the responsiveness.Highlighting the numerous modal(a) structures have-to doe with as advantageously as function of iron, oxygen and proton (Figure) shows the catalytic mutation required for cp450 oxidation reaction to pasture. The backrest of the substratum with low birle ferric CYP450 enzyme induces a change over in its restless site. This forget egresss the stability of the water ligand and lead displace it (shown in the diagram from a-b). Containing a superior spin heme iron the enzyme and substratum form a ferric complex. The change in negatronic utter pull up stakes chair in the justify and transfer of one electron from NADPH via electron transfer chain (reducing ferric heme iron to ferrous state) and t therefore decrement of the complex. The second electron is transferred when the complex reacts covalently wit h the oxygen forming a new ternanry complex. Initially the complex is an bad oxy-P450(diagram d), moreover this is reduced to produce ferrous hydrogen peroxide by a loss of an electron. This middling is concise lived and beares protonation twice resulting in a dismissal one water molecule. proscribed of the oxygen molecules resignd one in embodied in this water molecule and the remaining into the substratum. An another(prenominal) method of forming the iron-oxo intermediate is via the peroxide shunt which elimited step from C to F.Some of the third estate addition of oxygen molecule reactions which CYP450 dependent are know as epoxidation (of bivalent bond), N-hydroxylation, oxygen/nitrogen/ atomic number 16 de torrentlation, s-oxidation, dechlorination, oxidative desulfurisation and aromatic hydroxylation. strain they all follow the aforementioned(prenominal) regulation of adding oxygen molecule to the substrate. The diagram down the stairs provides an example of how these reactions are bear onredolent hydroxylation substrate loosely produces phenylic red-hots such(prenominal) as that visualisen on contour 3. The production of Phenol can be either via a non enzymatic rear passment or by Epoxide hydrolase and cytosolic deenthalpyase which leave behind finally give rise a catechol. The slope of hydroxylation depends greatly on the nature of the R- stem tie to the ring an electron withdrawing collection provide position the -OH base on the metha succession the electron donating ordain position it on the para or ortha. Aromatic hydroxylation besides involves a change in NIH shift, which involves the movement and shifting of the R conference 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. below such condition the aliphatic C-H) hydroxylation go away 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 legal age of drug metabolism is fundamentalally carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand situation clearly demonstrate just how much of drug metabolism is CYP450 3A debt instrument in comparison to other, accounting for roughly 50%. Metabolism of drugs stipulation orally are greatly refractory by CYP450-3A primarily because this enzyme is put forward in both the liver and catgut and thus providing a barrier for all drugs earlier they can drop the systemic circulations, differently commonly known as first gear question military unit. Upon entering the drugs are interpreted up via passive diffusion and/or served diffusion or brisk transport into the entercocyte where they can be metabolized by CYP450-3A. They can once over again be metabolized by the very same enzyme when they enter the li ver (hepatocyte) ,which impertinent the intestine in order to penetrate the systemic circulation it is unavoidable. This family of enzymes are also known to be cause of some(prenominal) salutary adverse cause as they are influenced by victuals and drug components, w wherefore drug-drug and drug-food interactions is an important factor.Flavin monooxygenasesSimilar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major cover 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. at once they have incur 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 center that any compound binding to the intermediate is a substrate to be metabo lized. The fact that this enzyme is able to remain abiding and lacks any need for amend ar straddlement and disorientation of the substrate gives it ability to withhold all the postcode required for the reaction to takes place and hence as soon as appropriate lipophilic substrate dies easy it starts the process immediately. Adverse fount moments 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 flak by the oxygen that is located at end of 4-hyroperoxyflavin. This is so followed by sectionalization of peroxide. The flavin monooxygenase catalytic cycle is finished once the real form of 4-hyroperoxyflavin has been regained using NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times undergo drop-off venture to its original parent form. intoxicantic beverage dehydrogenase and aldehyde dehydrogenaseThese families of enzymes are both atomic number 30 containing NAD specific and turn the reversible oxidation of inebriant and aldehydes respectively. sorted into 1-6 Alcohol dehydrogenase, are homodimer that experience in the soluble section of the tissue. It is mingled 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 road for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulting in adverse side effects mingled with alcohol and with certain analgesics drugs. Alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a eternal half life and fast absorption from the gut, methanol can result in series of painful side effects and metabolic back breakerosis, hence highlighting the importance of alcohol dehydrogenase. Similarly, aldehyde dehydrogenase catalysis the oxidation of aldehyde to its corresponding carboxyl acid. Class one of alcohol dehydrogenase plays a major subroutine in detoxification of anti cancer drugs. Alcohol dehydrogenase is also involved in reduction driveway of aldehyde or ketone back to its pharmacologically lively alcohol form.Monoamine oxidase and diamineLocated in liver, intestine and kidney as hardly a(prenominal) of its site, this membrane bound enzyme is change integrity into two classes in uniformity 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 alternate to tertiary amines that have alky group smaller than methyl group radical radical group. The general tool 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 either 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 utilise to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenetic substrates such as noradrenalin plot monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their common substrate is dopamine. quelling of monoamine oxidase has dour been of an amuse for scientist in word 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 diam ines in the same manner.ReductionThis tract of metabolism is enzymatically the least study in phase I and however 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 roadway in the mammalian tissue. This is due to the fact that the hundredyl group is very lipophilic, thus the lipophilicity allow be reduced and extermination is ensured as ketone is converted to alcohol.One of the major enzymes involved in this route is the NADPH cytochrome P450 reductase. Containing flavin angstrom 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 see 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. of course esters are much easier targets to esterase hydrolysis than amides. A very common amide substrate is a local anesthetic, Lidocaine and an antiepileptic drug known as levetiracetam. Catalyzing ester and certain type of amides are the group of enzymes referred to as carboxylesterase. This enzyme hydrolysis choline like ester substrate and procaine. As a rule, the more lipophilic the amide the better it be accepted as a substrate for this enzyme and thus eliminated. Esters that are sterically kiboshed are however much harder and drawn-out 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 exigent for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the one C tie 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 transgress of drug metabolism)Second agency of drug metabolism, involves introduinh of new dome 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 alignment reaction and its products are largely in industrious unlike those of phase 1. The side by side(p) reaction are major articulation 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 adenosine t riphosphate 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 soft touch electrophilic character (Principle of drug metabolism, 2007). Depending on the useable group fork up on the substrate Conjugation via methylation is broken downhearted to nitrogen, oxygen and sulfate methylation.O-methylationO-merthylation is the most common reaction that occurs for substarte containing the native (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to surface of the substituted group, the larger it is the bleaker 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. remote the above reaction, N-methylation consists of several enzymes, all of which are categorized in accordance to the specific type of amine substrate which they catalyze. Enzymes such as amine-N-Methyltransferase, nicotinamide-N-methyltransferase and histamine-N-methyltransferase are few examples. Despite the substrate specificity all the enzymes involved do however follow the same principle of transferring methyl fromcofactor s-adenosyl-L-methionine to the substrate.With drug substrates such as captoril, reactions of N-methylation can be broken down into two distinct types as illustrated in Fig 11. Reactions that have a low pharmacological significant deliver an in stiff 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 switch for a methyl group. On the other hand a more hydrophilic product and an effective reaction of detoxification is achieved with pyridine type (nitrogen atom) substrate. These substrate will result in a creation of positive change on the product (fig 7b) rather than an transpose process.Sulfate and phosphate legal jointuresulfate concurrence is one of the most important reactions in biotransformation of steroids, effecting its biological activates and diminish 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. loose ly 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 organise 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 efficacy for the reaction. In human there is two class, SULT 1A- 1E and SULT 2A-2B, individually of which will have different specificity yet with overlaps. This enzyme acts on both endogenic as well as exogenous compounds as long as they possess an alcohol (less family relationship with varying product stabilities) or phenol (products are stable arly sulfate esters with a high affinity). Substrates are generally of medium sized, highly ionised and hydrophilic, hence excreted easier via urine. The rate of this pathway is determine 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 niggardliness and 3-phosphoadenosine 5 becomes rate limiting. The sulfate conjugation will produce ester sulfate or sulfamide some of which will undergo further heterolytic reaction leaders to electrophilic substrate and hence toxicity.Unlike the sulfate conjugation the phosphate conjugation is less common unless the drug in question is antitumor 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 linked metabolite in the urine. This pathway is important due to the fact there is a high accessibility of glucucronic acid, huge substrate specificity and the simple 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 indeed 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 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, give has been done to divide them into quartette 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, contractable polymerizati on of acetylation function has meant that the rate of reaction and item of toxicity will differ in accordance to the polymers. closely acetylation will have result in a fast conversion and elimination while slow acetylators will have the opposite effect and will lead to build of unconjugated compounds in the blood and hence leading to toxicity.Conjugation with co-enzyme A unremarkably using this pathway are the carboxylic containing which are activated into an intercede 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 am ino 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 utilize 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 change and reduced form hence enablin g it to accept a wider range of substrate. The reduced form of glutathione is able to act as a protect agent as it removes bump 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 substantially 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, 7 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 survey 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 g lutathione 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 wanting CH2 group, which the glutathione substitutes as it becomes added on to the carbonyl as shown in fig 12. Nucleophilic re-sentencing 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 bragging(a) rise to a protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via vapour catalyzed by acid prominent 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 create 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 grouchy drugs, make 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 ref erred to as pro-drugs and will be considered in greater detail later.Drug metabolism is pause 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. F irst we will examine the metabolism of naproxen (6-methoxy-a-methyl-2-naphthyl acetic acid). Naproxen is a wide used NSAID, possible of blockage both cyclo-oxygenase isoforms 1 and 2, therefore making it a non-selective inhibitor of these isoforms. Rheumatoid arthritis and degenerative joint disease are the main designer for use of naproxen, which is administered orally as the S-enantiomer.This item 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 means of elimination is through the urine. The contiguous major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An mobile 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 working 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 make more water-soluble hence soft 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 na proxen-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 blanket(a) 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 automobile trunkProcesses 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 excretion via the kidneys. The basic understanding of drug metabolism is paramount to ensure drug optimisation, maximum therapeutic benefits and a reduction in adverse effects. Essentially drug metabol ism 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.Inacti ve drugs with the ability to reconvert to the active parent drug once metabolised to exert their therapeutic actions are defined as prodrugs. They are classified depending on the site of conversion and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within the body, compared to their active metabolites. Individual drug metabolism may be affected by variant factors, such as, age or sex. Drug metabolism can cause an increase in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this toxicity can occur in Phase I metabolism e.g. acetaminophen. However, in some circumstances toxicity occurs in Phase II e.g. zomepirac, polymorphism can also cause idiosyncracity of certain drugs to be toxic.1.1 Phase IPhase one, otherwise known as drug biotransformation pathway is generally broken into oxidation, reduction and hydrolys is. 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 100 0 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 invol ved 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. Ou t 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 rearrangement or by Epoxide hydrolase and cytosolic dehydrogenase which will ultimately give rise a catechol. The position of hydroxylation depends greatly on the nature of the R- group attached to the ri ng an electron withdrawing group will position the -OH group on the metha while the electron donating will position it on the para or ortha. Aromatic hydroxylation also involves a change in NIH shift, which involves the movement and shifting of the R group to an adjacent position during the oxidation. It is important to note that certain substrate for aromatic hydroxylation can also be oxidized via the aliphatic (C-H) hydroxylation. Under such condition the aliphatic C-H) hydroxylation will oxidize it. Aliphatic dehydrogenation can also occur involving electron transfer to the CYP450.Currently more than 50 CYP-450 has been identified in human, however the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand side clearly demonstrate just how much of drug metabolism is CYP450 3A responsibility in comparison to other, accounting for roughly 50%. Metabolism of drugs given orally are greatly determined by CYP450-3A primarily because this enzyme is present in both the liver and intestine and thus providing a barrier for all drugs before they can enter the systemic circulations, otherwise commonly known as first pass effect. Upon entering the drugs are taken up via passive diffusion and/or facilitated diffusion or active transport into the entercocyte where they can be metabolized by CYP450-3A. They can once again be metabolized by the very same enzyme when they enter the liver (hepatocyte) ,which unlike the intestine in order to reach the systemic circulation it is unavoidable. 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 monooxygenasesSimilar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major role in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also ox ygen 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 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 lo cated 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 metab olism. 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 as few of its site, this membrane bound enzyme is divided into two classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deamination to aldehyde, these enzymes are flavin containing enzymes and within their cysteinyl residue the flavin is linked to the covalently bounded flavin via a thioether. Monoamine oxidase has several substrates, ranging from secondary to tertiary amines that have alky group smaller than methyl. The general mechanism for this enzyme is the two electron oxidation shown 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 com mon 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 lipophilicity will be reduced and elimination is ensured as ketone is converted to alcohol.One of the major enzymes involved in this pathway is the NADPH cytochrome P450 reductase. Containing flavin adenine di nucleotide 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 as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and slower to be hydrolysed and will usually be eliminated unchanged at a high percentage such as that for atropine, eliminated 50% unchanged.A very good example of esterase enzyme is the paraoxonase. The hydrolysis of substrate such as phenyl acetate and other acyl esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are imperative for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the carbon attached to the oxygen resulting in a formation of tetrahedral orientation. The presence of a hydrogen donor to the improvers the leaving group abilities is the final requirement.1.2 Phase II (Second part of drug metabolism)Second part of drug metabolism, involves introduinh of new ionic chemicals on to the substrate (including the metabolites from phase I) in order to increase its water solubilyt for elimination. This phase is usually refered to as conjugation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major conjugation of phase II.Methylation is the transfer of methyl group to the substrate from cofactor s-adenosyl-L-methionine (fig 9). S-adenosyl-L-methione is an active intermediate that receives a transferred methyl group from methionine after its linkage with ATP in presence of adenosine transferase enzyme. 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 pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to size of the substituted group, the larger it is the slower the rate of reaction degree of acidity of the catechol group itself.N-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 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 product (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 acti vates 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 wi th 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 the drugs involves a condensation reaction and hence release of water, while the conjugate replaces the hydrogen on the -OH group. Present in the ER uridine-5-diphosphae-alpha-D glucoronic acid is produ ced 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 i nvolved 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 se rious 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 wid e 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 protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via dehydratio n 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 particular drugs, makin g 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 discusse d 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 met abolite formed can occasionally become active. This reaction is facilitated by the superfamily UDP-glucuronosyl transferase (UGT) enzymes. The major UGT isoforms found in the liver are 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7 2B10, 2B15, 2B17 and 2B28. The isoform 2A1 is found mainly in the nasal epithelium, while 1A7, 1A8 and 1A10 are only localised to the gastro-intestinal tract. UGT acts as a catalyst enabling glucuronic acid to bind to naproxen at the carboxylic acid group via covalent bonding.It has been found that all UGT isoforms contribute to the conversion of naproxen to its metabolite naproxen-AGLU, except UGT-1A4, 2B4, 2B15, and 2B171. This reaction produces a highly polar glucuronic acid molecule bound to naproxen. Its main mode of elimination is through the urine. The next major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An unstable metabolite is formed during this process, h owever it is hydrolysed immediately to DM-naproxen. The enzymes involved in this reaction are cytochrome P450 1A2 and 2C9 from Phase I.Once DM-naproxen has formed it is glucuronidated with the help of UGT enzymes 1A1, 1A3, 1A6, 1A9 and 2B7 and converted to its acyl glucuronide. UGT-2B7 is a high affinity enzyme and so has a high activity in this process, as does UGT-1A6. UGT-1A4, 2B15 and 2B17 do not contribute to the acyl glucuronidation process1. DM-naproxen is also converted to phenolic glucuronide this is formed by the UGT enzymes 1A1 and 1A9. Enzymes UGT 1A3, 1A6 and 2B7 appear to play no part in this reaction. UGT 2B7 works well in glucuronidating the carboxylic acid moiety in particular drugs however it is unable to glucuronidate the phenolic group, so for this reason is not involved in forming phenolic glucuronide.The aim of hepatic metabolism is to ensure metabolites are made more water-soluble hence easily excreted. All metabolites formed from naproxen are water soluble an d 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