Wednesday, November 27, 2019

Trabajo 4 Bimestre Essays - DraftCarmen Herrera,

Trabajo 4 Bimestre Ana Christina Vos Garcia de Alba 2B N.L #24 Materia: Redaccion Maestra: Carla Rivero Fecha de entrega: 20/04/16 7480300top 3460099000 Aun lo recuerdo como si hubiera sido ayer, todavia puedo revivir la emocion y felicidad que senti ese dia. Tenia yo 3 anos y vivia en Holanda. Es dificil pensar que han pasado mas de 12 anos y que la experiencia sea aun tan tangible en mi mente. Era pleno verano, la mejor temporada en Holanda. Consideremos que en Holanda por casi 10 meses al ano hace frio y que la mayor parte del tiempo llueve. Pero al llegar el verano toda la gente y los lugares se transforman. Las personas se visten con ropa mas ligera y colorida, las mujeres finalmente muestran los pies al caminar en sus sandalias, los hombres permanecen felizmente por horas sentados tomando una cerveza en una de las muchas terrazas que los restaurantes abren en esta temporada ; todo mundo es feliz, todos incluyendo hasta los ninos. A bandonamos nuestro capullo para convertirnos en hermosas y alegres mariposas! Llevaba dias esperando este gran dia. En mi mente de 3 anitos no parecieron dias, parecieron interminables meses, pero al fin habia llegado el gran momento. Ese dia iria junto con mi prima Linde al mas increible parque de atracciones de toda Holanda, el Ef teling , un parque como ningun otro que lleva existiendo desde 1952 con algunas modificaciones claro. Lo que distingue a este parque de cualquier otro es que todo el tema gira alrededor de las fabulas y fantasia Ya llevabamos horas en el parque, disfrutando de cada momento, y de repente mi prima Linde y yo vemos a Pardoes a lo lejos. Gritamos las dos, y corrimos hacia el. Mis tios, papas de mi prima Linde, con quienes fuimos en esta ocasion al parque, apenas si nos podian seguir el paso. Corrimos, lo abrazamos y nos regalo a cada una un globo que conserve por meses hasta que se desinflo por completo. Pardoes se arrodillo, me abrazo y en ese momento mis tios nos tomaron la foto a mi prima y a mi . Oh, que gran momento. Si pudiera describir la felicidad con una foto, esta seria la foto elegida. En la imagen destacan unos globos amarrados a un un palito blanco que teniamos en la mano mi prima y yo. Los glob os tienen la cara de Pardoes , el personaje tematico del parque, que es un duende que va vestido como arlequin, trae puesto una especie de vestido color rojo, y a la cintura trae amarrado un gran cinturon color marron, sus zapatos son rojos y terminan en forma puntiaguda, trae un collarin en el cuello de color amarillo con picos y de este van colgando unas borlitas , el sombrero que trae es color rojo, es de gran tamano y tiene colgado 3 campanas que suenan cuando este camina. Su cara se caracteriza por unos ojos muy grandes y abiertos de forma ovalada , una sonrisa amplia y unas chapas muy rozadas. Teniamos 3 anos aproximadamente mi prima y yo, ella es tan solo 6 meses mayor que yo, y siempre fuimos muy unidas y buenas amigas. Nuestro caracter es muy diferente, pero precisamente esto hace que nos complementemos perfecta mente desde chiquitas. Fisicamente mi prima era gera con pelo lacio y corto, yo con pelo marron y chino. En la imagen t engo puesto un overol de mezclilla con un bordado de Minnie M ouse, combinado con una playera y tenis rosas. Mi prima trae un pantalon rosa claro , una playera con rayas blancas y rosas, y unos zapatos de color negro. Detras sale Pardoes abrazandonos par a tomar nos la foto. Se pueden ver al fondo unos adoquines de color rojo oscuro, que eran el suelo. Resaltan las caras que teniamos mi prima y yo de felicidad, y gusto al tomarnos una foto con e l unico e inigualable Pardoes . Grandes sonrisas y colores forman esta imagen que tan buenos recuerdos me trae. Ese dia termino, de seguro acabamos rendidas y dormidas en el trayecto a la casa, pero con memorias que permanecerian por siempre con nosotras. Los anos pasaron y e sta pasada Navidad del 2015

Sunday, November 24, 2019

PG, McDonalds and KFC Companies in the Saudi Arabian Market

PG, McDonalds and KFC Companies in the Saudi Arabian Market Management differs from one organization to another due to the differences in size and income. Multinationals, SMEs, and global organizations have different styles of management since they deal with different cultures, employees, and clients in various areas of investment.Advertising We will write a custom coursework sample on PG, McDonalds and KFC Companies in the Saudi Arabian Market specifically for you for only $16.05 $11/page Learn More At the global and multinational level, an organization has to adjust to international management standards in order to be successful in business. Organizations like McDonalds, KFC, and PG operate at global and multinational levels and this forces them to promote international human resource and ethics management (Shankar 12). The purpose of this discussion is to analyze the position of PG, McDonalds, and KFC in the Saudi Arabian market. PG’s Foreign Investment in Saudi Arabia PG is a multinational organization wit h branches in most parts of the world. Initially, it avoided Saudi Arabia due to the stringent business rules that the government had set on people. After opening up the market to the rest of the world, many organizations, including PG, showed interest in Saudi Arabia. PG chose Saudi Arabia since the country is a key business hub for the Middle East. Many people associate with Saudi Arabia when conducting oil deals, and they would probably take interest in other industries like PG operating in the country. Secondly, PG considered the availability of raw materials for its products.Advertising Looking for coursework on business economics? Let's see if we can help you! Get your first paper with 15% OFF Learn More Saudi Arabia has affordable materials extracted from crude oil to make candles, soap, and other products that PG manufactures. Besides availability of affordable labor, ready buyers, and raw materials, PG opted for Saudi Arabia due to the availability of distributors of its products. Abudawood Trading Company Limited is a distributor of PG products and the company formed a joint venture with Proctor and Gamble to increase awareness of PG products in Saudi Arabia (Buckman 24). Finally, Saudi Arabia promotes growth of many organizations in terms of publicity and income generation owing to its huge population. Pepsis Improvement in Saudi Arabia After entering the Saudi Arabian market, Pepsi identified various strategies of survival in the market that the government initially closed to foreign investors. After a conclusive SWOT and PESTEL analysis, Pepsi developed workable measures of remaining relevant in the competitive economy. Pepsi invests in quality marketing, branding, and packaging since its greatest rival Coca-Cola equally provides similar services. In order to be unique, the company introduced Pepsi diet, which has fiber that helps in reducing weight gain, and improving health. Health consciousness is a major concern in Sau di Arabia, which the Muslim religion strongly supports. In Saudi Arabia, Islam deters residents from consuming alcohol or pork, as they consider such foods as unhealthy. The same applies to high calorie content foods and soft drinks that contain high levels of sugar, preservatives, and carbon.Advertising We will write a custom coursework sample on PG, McDonalds and KFC Companies in the Saudi Arabian Market specifically for you for only $16.05 $11/page Learn More Pepsi realized such concerns and developed Pepsi diet to increase consumer consciousness about health while enjoying soft drinks. In its adverts, Pepsi uses Saudi locals and celebrities in order to increase consumer association with the products that it manufactures in the country (Cho and Moon 41). Recommendations for KFC in Beating Competitors KFC needs to learn the things that are unique to Saudi Arabians that other countries do not consider in order to provide better services as consumers expect . For instance, KFC should not ignore religion, dressing, language, and etiquette, as they are vital to Saudi residents. KFC has strengths over competitors like Albaik since it has many branches across the world. Albaik has no branches outside Jeddah, which reduces its chances of gaining publicity over KFC. Another strength that KFC needs to capitalize on is the fact that Albaik does not respond to concerns raised over fast foods. KFC equally sells processed fast food, but it serves portions of salads, non-alcoholic wines, fresh juices, and low calorie foods. Albaik does not recognize the significance of changing the styles of manufacturing foods owing to transforming consumer demands. This gives KFC an advantage over rivals in the Saudi Arabian market, which the company needs to recognize. KFC needs to employ many Saudi residents instead of importing workers from the US. Corporate social responsibility is about providing employment opportunities, tax payment, and ability to care fo r the social and geographic environments (Sims 32).Advertising Looking for coursework on business economics? Let's see if we can help you! Get your first paper with 15% OFF Learn More This will definitely make KFC trustworthy to prospective consumers and will enable it gain competitive advantage over competitors. McDonald Company A multinational company operates in more than one country in terms of establishing different branches across the world. A global company has a single headquarter, but uses technology to respond to consumer needs. In essence, McDonald is a global multinational company headquartered in the US, but with many branches across the world. It has over 34,000 outlets operating in different countries in the world. Moreover, it has franchises in the US and communicates to other clients through social media, its website, and online marketing tactics. This makes it a global company that uses technology to interact with consumers from different parts of the world. McDonald has branches in the US, the UK, parts of Africa, Asia, and Middle East (Pride, Hughes, and Kapoor 84). Physical investment and the ability to learn new cultures by paying for licens es in countries of investment make it a multinational corporation. Companies combine both global and multinational techniques in order to acquire the highest number of consumers willing to purchase products from the company. Being a multinational company is more costly as opposed to being a global company per se (Pride, Hughes, and Kapoor 82). A global company spends limited resources in marketing, tax payment, and shipping. On the other hand, it becomes difficult to develop trustworthy relationships with the target population. Companies and Internationalization Internationalization links SMEs to multinationals making it easy to share information, resources, or even form mergers. PG entered the Saudi Arabian market in 1955, and this expanded its international connections. It merged with Abudawood Trading Company Limited, which expanded its market share in the country. Saudi Basic Industries Corporation (SABIC) is an example of an organization that benefits from internationalization. It established a strong presence in the Gulf region and Asia even though the corporation does not deal in oil. Saudi Arabian Aramco is another example of an organization that strives to attain international recognition (Shankar 42). These organizations realized that cultural barriers deter effective trade between Saudi Arabia and the international countries. Such corporations deal with foreign countries in Europe and America differently since cultural appreciation is an important element of business management. FDI vs. Portfolio Management Foreign Direct Investment (FDI) refers to the possibility of an enterprise to own 10%+1 of an overseas business investment. On the other hand, portfolio management refers to a company’s investment in its own business. For instance, when PG trades with Abudawood Trading Company Limited, it has investments in a foreign company, Saudi Arabia. FDI Advantages Companies easily develop mutually beneficial relationships with other countries throug h FDI. This enables them to brand position their commodities in the country given that the other company that understands the prevailing market conditions can always market their commodities of the foreign company. Increase in international relations promotes sales, which increases profits for an organization (Pride, Hughes, and Kapoor 61). FDI makes it easy for a foreign organization to understand the political, social, and political environments of the target market before opting to invest in the country completely. Corporations get competitive advantage over rivals that operate independently. FDI is important for the local and foreign companies involved in the agreement. FDI Disadvantages FDI involves interactions between different organizational cultures, which might cause conflicts between the involved organizations. The corporation that owns over 10% of the foreign company’s assets may dominate the group while adding no value to the union. FDI is about risk taking in co mparison to portfolio management that many organizations from advanced countries use. Under portfolio management, people who understand the organizational culture including financial organizations and the government play a role in ensuring that the invested money is safe. Finally, through FDI, it can be difficult to transform some assets into cash when emergencies occur. PG’s FDI in Saudi Arabia Proctor and Gamble realized that Foreign Direct Investment (FDI) is a responsibility and an opportunity at the same time. In essence, while taking an advantage of the investment opportunity, it needed to exercises various precautions. First, PG assessed the environment of investment, which included Saudi Arabian political, social, technological, and economic position. This enabled the company to understand that the negative environmental factors were fewer as opposed to the positive elements. Notably, the study gave PG good reasons to seek a distributor (Shankar 33). Secondly, PG made an individual entry into the new market and assessed all other organizations, but settled on Abudawood Trading Company Limited. This follows its ability to trust the other company after assessing their performance in the market since inception. Additionally, PG officials met with Abudawood Trading Company Limited officials for negotiations. PG trusted Abudawood Trading Company Limited after working with it as a distributor for a long time. During negotiations, PG considered the importance of signing agreements that favor both firms. The greatest element of consideration for PG was sustainability in Saudi Arabia and the possibility of increasing the consumer base. PG considered a growth opportunity in Saudi Arabia, and since Abudawood Trading Company Limited understood clearly the market conditions, it definitely provided the best guidance to PG. Finally, PG looked at diversity, availability of affordable raw materials, availability of human resources, and costs of production (Dunni ng 18). Egypt’s Economic System Closed economic systems normally prevent foreign investors from establishing corporations in their countries. Egypt is the exact difference of a closed system since investors can easily establish brands in Egypt, but the challenge is that nobody cares about investment activities. Political instability and poor trade policies make it difficult to trust Egypt, especially when dealing with FDI cases. Egypt has a laissez faire system in which nobody really controls the economy (Kaplan 74). Studies indicated that it has the unrestricted system in which many government bureaucrats use taxes for personal gain. Many middle class residents pay taxes, but few rich people benefit from such efforts. Egyptians need thorough knowledge on financial management so that they can take control of the economy instead of leaving it to a few bureaucrats. Uncontrolled markets have significant impacts on Egyptians including increase in unemployment rates, increase in t axation, inflation, and increase in national debts. Egypt’s Benefits by Gaining Admission to GCC Gulf Corporation Council (GCC) consists of oil producing countries that invest within the Gulf area, Europe, and Asia. GCC provides rules that govern member states in order to establish high discipline levels. GCC ensures that the involved countries ensure that conflicts within a country do not interfere with trade. This helps in stabilizing the economy even in moments of conflict or inflation. Egypt needs to join GCC in order to acquire the status of other states like Kuwait, UAE, and Saudi Arabia. GCC sets clear standards concerning management of oil reservoirs and companies, and this reduces confusions over ownership of various oil fields. Hazem al-Beblawi, Egypt’s deputy prime minister, displayed interest in the proposal that seeks to incorporate Egypt in GCC. He understands that Egypt needs to interact with countries that will support it with financial information. Suc h levels of empowerment will help the country reduce its budget deficit and promote self-employment in order to reduce the unemployment gap (Kaplan 74). Risks of FDI in Egypt As mentioned earlier, FDI is a risk measure, but a corporation needs to assess the political and socio-economic environments. The past political unrests in Egypt made the country economically unstable. Government bureaucracy and budget deficit in Egypt make companies unstable and a merger with such companies poses a threat to foreign corporations. Companies that apply portfolio management may succeed in their operation. For instance, when inflation occurs, a company can sell its assets quickly and recover the funds (Dunning 47). An unstable economy like Egypt keeps changing and FDI becomes risky since it would be impossible to recover invested funds in another corporation that might be experiencing losses (Kaplan 19). FDI is only possible in closed and capitalist markets that have certain levels of control. The Egyptian economy lacks proper management, thus posing security risks for investment-oriented institutions. Buckman, Greg. Globalization tame it or scrap it?. Dhaka [Bangladesh: University Press ;, 2004. Print. Cho, Tong, and Hwy Moon. From Adam Smith to Michael Porter evolution of competitiveness theory. Singapore: World Scientific Pub., 2001. Print. Dunning, John H.. Multinational enterprises and the global economy. Wokingham, England: Addison-Wesley, 19921993. Print. Kaplan, Leslie C.. Economy and industry in ancient Egypt. New York: PowerKids Press, 2004. Print. Pride, William M., Robert James Hughes, and Jack R. Kapoor. Business. Sixth ed. Mason: South-Western Cengage, 2012. Print. Shankar, Venkatesh. Handbook of marketing strategy. Cheltenham, UK: Edward Elgar Pub., 2012. Print. Sims, Ronald R.. Ethics and corporate social responsibility why giants fall. Westport, Conn.: Praeger, 2003. Print.

Thursday, November 21, 2019

Quantitive methods Assignment Example | Topics and Well Written Essays - 2750 words

Quantitive methods - Assignment Example We shall first conduct an informal graphical analysis to get a feel for what to expect and then move on to formal tests for stationarity. We start by looking at the time plots of the two given series. Figure 2: share price of Korean Airlines Figures 1 and 2 present the time plots. Evidently, both series exhibit a gradually rising trend and some moderate persistence properties. This reflects that neither of the series are stationary. They also seem to reflect similar patterns of persistent volatility. Now, we turn to look at the first differences of the two series. Figure 3: The Korean Stock Exchange stock price index in first differences Figure 4: price of Korean Airlines in first differences. From figures 3 and 4, we find that neither series exhibits any patterns or trends. They seem to fluctuate randomly around zero. Thus, both the series of 1st differences seem to be stationary around a zero mean. Thus our preliminary graphical analysis reflects that both the series are integrated of the first order. Formally to evaluate the validity of these claims, we run Augmented Dickey Fuller (ADF) tests on the levels and the 1st differences of the two series. ... Augmented Dickey-Fuller Test Equation Dependent Variable: D(LKO) Method: Least Squares Date: 04/09/12 Time: 13:53 Sample (adjusted): 1/08/1997 12/14/2011 Included observations: 780 after adjustments Coefficient Std. Error t-Statistic Prob.  Ã‚   LKO(-1) -0.003394 0.003258 -1.041768 0.2978 C 0.024682 0.022454 1.099231 0.2720 R-squared 0.001393   Ã‚  Ã‚  Ã‚  Mean dependent var 0.001348 Adjusted R-squared 0.000109   Ã‚  Ã‚  Ã‚  S.D. dependent var 0.044155 S.E. of regression 0.044152   Ã‚  Ã‚  Ã‚  Akaike info criterion -3.399783 Sum squared resid 1.516653   Ã‚  Ã‚  Ã‚  Schwarz criterion -3.387836 Log likelihood 1327.915   Ã‚  Ã‚  Ã‚  Hannan-Quinn criter. -3.395188 F-statistic 1.085281   Ã‚  Ã‚  Ã‚  Durbin-Watson stat 2.039111 Prob(F-statistic) 0.297843 Table 1 above presents the results of running an ADF test on the lko series. The choice of optimal lag is automatic based on the Schwarz information criterion or SIC. Note that the null hypothesis is that the series has a uni t root. The relevant portions have been highlighted for convenience. The t-statistic is smaller in absolute terms compared to the critical value, and the associated p-value is 0.74>0.05. Therefore, we fail to reject the null hypothesis. Thus, this implies that the series of levels of the lko is non-stationary. Now, we take first differences of the series and test its stationarity properties. This is done in table 2. Table 2: testing stationarity of the 1st differences of lko Null Hypothesis: D(LKO) has a unit root Exogenous: Constant Lag Length: 0 (Automatic based on SIC, MAXLAG=20) t-Statistic   Ã‚  Prob.* Augmented Dickey-Fuller test statistic -28.52751   0.0000 Test critical values: 1% level -3.438518 5% level -2.865035 10% level -2.568686 *MacKinnon (1996) one-sided p-values. Augmented Dickey-Fuller Test Equation Dependent

Wednesday, November 20, 2019

Texas Government Assignment Example | Topics and Well Written Essays - 500 words

Texas Government - Assignment Example Likewise, the partisan elections tedious, and can cause straight ticket voting together with electing judges based on the familiarity of the names. The long ballots can be challenging for the voters because it is difficult for the electorate to follow up on the comprehensive lists of the candidates. Due to the aforementioned challenges in the partisan elections, it is significant for the Texas State to adopt a system in which the governor appoints the judges. The death penalty is immoral and expensive, and thus the Texas State should abolish the capital punishment. Newell, Prindle, and Riddlesperger argue that the expense of executing a criminal exceeds $ 2 million, and the punishment achieves nothing in terms of deterring the potential criminals in engaging in crime (340). Exploring the issue of the death penalty from the moral point, it is unethical and immoral to terminate the life of a person. The capital punishment degrades humanity, and inflicting death on persons does not necessarily control crimes. Therefore, it is important for the Texas State to explore other alternatives of punishing the wrongdoers instead of pursuing the death penalty. It is less costly for the Texas State to practice life imprisonment as opposed to the expensive capital punishment. Sentencing the convicted people to the life in prison without the possibility of parole is a plausible alternative. Such a sentence will enable the Texas State to reduce the many funds that tend to maintain the costly death penalty system. The nomination of the city candidates to run for the office in Texas State is essential in facilitating the electorates to know and analyze the ideologies of the individual candidate. In this respect, the Texas State should endeavor to practice partisan elections in which a political party nominates the candidates to run for the office. Newell,

Sunday, November 17, 2019

Campaign review 2 Essay Example | Topics and Well Written Essays - 2250 words

Campaign review 2 - Essay Example Worth noting about the topic of advertisement is that various studies have been conducted to determine the influence humor has in terms of persuasion. In the past, it has been established that customers or prospects seldom responds to mere information meant to advertise. Conversely, when an advertisement has humor included, it inevitably catches the attraction of many people. Consequently, many tend to seek more information regarding the product or service being advertised. In the end, there is a high possibility of the client purchasing the service (Cialdini, 2001). Having presented a campaign review on Old Spice’s â€Å"Your man can smell like me† advertisement, this paper will analyze how one theory of communication process was appropriately applied. One theory that was evidently applied in the campaign is Richard Petty’s and John Cacioppo’s Elaboration Likelihood Model (ELM). ELM theory is one that Richard Petty and John Cacioppo developed in the 70s that sought to explain how prospects respond to advertisements. The theory explains the path taken in the shaping, formation and reinforcement of attitudes through persuasive arguments. In essence, the theory claims that once information is availed to a person, there is some inevitable elaboration level that tends to occur. It explains that persuasion takes one of the two paths: Central or Peripheral paths. Each of these is dependent on a couple of things exhibited by the prospects. Four principles are used to analyze which path a buyer or a prospect has taken (Payne, 2008). These include elaboration, attitude, information processing and the strength of the attitude that has been reinforced, and this section will highlight how the theory is analyzed. In the case of Central path, a client has to understand the message behind an advert in order to take this side. In contrast, when the elaboration is limited the most likely

Friday, November 15, 2019

Processes of Drugs Metabolism in the Body

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

Tuesday, November 12, 2019

Review of a Leader Movie Armageddon Essay

1. Style Of Leadership The style of leadership portrayed by Bruce Willis was decisive and with full conviction, in the best interest of everyone under his care and jurisdiction as shown below. a) As a father, he undertook the sole responsibility of bringing up his daughter from young, after his separation from his wife. He brought her everywhere he went and when she got romantically involved with one of his workers, he showed much concern and took actions in the interest of his daughter’s future. b) As a company boss, he was decisive in terminating the services of his best worker, for taking matters in his own hands and thus jeopardizing the safety of the other workers. He did not tolerate any insubordination and commanded everybody’s respect. c) As a project team leader for NASA, he showed great concern for all humanity and thus, agreed to undertake the assignment. This decision showed his compassion and his willingness to make the ultimate sacrifice for the sake of others. As he was knowledgeable and showed great leadership skills, even NASA staff listened to him. This emphasize the fact that a good leader is able to influence and guide everyone, through exemplary actions and compassion for others. d) His willingness to make the ultimate sacrifice and switch places with his worker in staying back to detonate the bomb summarizes all his leadership qualities. As a father, he was more concerned for his daughter’s future and happiness and thus switched place with his worker, even though he realized that by doing so, he would die. As a company boss and the project leader, he felt that it was his responsibility to ensure that the job was done well and his compassion for the human race led him to make the ultimate sacrifice. 2. Leadership Communication Strategy The communication skills and strategy showed by Bruce Willis in the movie was very well portrayed. He was strict but fair. He communicated effectively at all levels and strategized it to ensure that it achieved its desired results, as shown below. a) He was initially very upset when he discovered his daughter’s affair with his worker, but later showed his acceptance without even letting them know. This is strategy. by showing his worker his disapproval initially, it makes his worker realize that Bruce Willis was very much concerned and would do anything to protect his daughter’s future. but as depicted at the end of the movie, it showed how Bruce Willis finally admitted his approval and was even willing to sacrifice his life for them. This is effective communications strategy. b) As the project leader, he showed conviction and determination to get the job done, even when faced with extreme situations. He reprimanded his staff accordingly when necessary and allowed them some recreations when needed to. This shows great strategy and very effective communications. When earth lost faith in him, he managed to persuade the commander to disarm the bomb. When he switched places with his worker to detonate the bomb, nobody suspected he would do so. He managed to strategize his communications well and achieved his target, even though he knew that by doing so, he would die. This was the ultimate strategy of a leader, leading by example and good communication skills. 3) Personality Of A Good Leader Through out the movie, Bruce Willis was portrayed as a leader with a good and humble personality, who was intelligent and critical with his words and actions. he was depicted as a very responsible father, a caring company boss and also a convicted project leader as described below. a) As a responsible father, he cared for his daughter all by himself, even with his hectic work schedule and the dangerous nature of his work. He loved his daughter very much and was very protective of her well being and future. b) As a company boss, he was well liked and well respected by all his workers. He did not hesitate to terminate his best worker when he jeopardized the safety of the other staff, thus confirming that he was fair, but strict, and this applied to all. c) As the project leader, he showed great conviction and determination. His ability to make decisive decisions and actions showed his leadership qualities and his ultimate sacrifice showed that he was a leader with great compassion for others without any regards for his own well being. 4) Motivation A good leader is always able to motivate all by his exemplary actions and effective communications. This was well depicted in the movie. It described how a good leader can have appositive effect on others and can turn failures into success, danger into safety and despair into joy as portrayed by Bruce Willis. a) He managed to motivate and convinced his daughter to allow him to undertake the assignment, even though it might cost him his life. Even though the movie does not depict much about his relationship with his daughter, we can imagine how much his motivation affected his daughter’s willingness to follow him everywhere he goes. Even though her role in the project was minimal, it showed how motivated she was, in trying to ensure that the project was successful. This was portrayed in scenes where she had confrontations with the ground crew. b) As a company boss and project leader, he managed to persuade his staff to follow him and inadvertently, put their lives in danger. Even then, they were willing to do so, through his motivations and his communications skills. Throughout the assignment on the asteroid, he played the part of the motivator, never giving up and never despaired, even though he had lost some of his men, who were also his closest friends. How he managed to persuade the commander to defuse the bomb prematurely, was the best example of a good motivator in action. The words he used to convince the commander and how he managed to persuade him was very effective and only a good leader would be able to achieve such a task. To be able to ask someone to put his life on the line and make the ultimate sacrifice for you, requires all the attributes of an exceptional leader. 5. Leadership Management Only a good leader would be able to manage well. There is a danger of a leader becoming a dictator, if he or she is does not have good management skills. These skills needs to be taught and practiced. In the movie, Bruce Willis plays the part of a father, a boss, and later a project leader. As a father and a boss, he had acquired the management skills and experience to be a good father and a caring boss, and applied these management skills as a project leader, as shown below. a) Even though it was not depicted, he managed to bring up his daughter to be a well educated and responsible person, who could contribute his company. Even under stressed situations, he managed to manage his daughter’s personal affairs and ultimately, ensured that she would be well taken care of, even when he was no longer alive. b) He would not be the boss of the company if he was not a good leader with good management skills. Thus, he was able to manage his team and all others in his attempt to ensure that the assignment was successful. As a leader, he managed to control all personnel under any situations. The fact that he managed to save the world in the movie, after going through extreme conditions and situations and even a near failure, shows that through good leadership management, you can achieve every success. In summary, there is no such thing as a born leader. Good leadership qualities needs to be learned and practiced. Anybody can be a leader but not everyone can be a good leader. The movie â€Å"Armageddon† is about a good leader, as described above. It portrayed how 1 man, who possessed all the right attributes, is able to successfully complete a near impossible mission and achieve the desired results and thus saving the world. This movie might seem unreal, but the message behind the movie is very clear. A good leader is able to affect the lives of other people in a positive way. It may be only one life or it could be billions of lives. The fact is, we could apply the message of this movie in our daily lives. We should all try to be good leaders and have good leadership qualities, for the best interests of ourselves, our family, our race, our religion and ultimately, our nation.

Sunday, November 10, 2019

Perception towards mutual funds Essay

Abstract: Mutual Funds provide a platform for a common investor to participate in the Indian capital market with professional fund management irrespective of the amount invested. The Indian mutual fund industry is growing rapidly and this is reflected in the increase in Assets under management of various fund houses. Mutual fund investment is less risky than directly investing in stocks and is therefore a safer option for risk averse investors. Monthly Income Plan funds offer monthly returns and invest majorly in debt oriented instruments with little exposure to equity. However it has been observed that most of the investors are not aware of the benefits of investment in mutual funds. This is reflected from the study conducted in this research paper. This paper makes an attempt to identify various factors affecting perception of investors regarding investment in Mutual funds. The findings will help mutual fund companies to identify the areas required for improvement in order to creat e greater awareness among investors regarding investment in mutual funds. Introduction A Mutual Fund is a trust that pools the savings of a number of investors who share a common financial goal. The money, thus collected, is then invested  in capital market instruments such as shares, debentures and other securities. The income earned through these investments and the capital appreciation realized is shared by its unit holders in proportion to the number of units owned by them. Thus a Mutual Fund is the most suitable investment for the common man as it offers an opportunity to invest in a diversified, professionally managed basket of securities at a relatively low cost. Monthly Income Plans or MIPs invest maximum of their total corpus in debt instruments while they take minimum exposure in equities. It gets benefit of both equity and debt market. These schemes rank slightly high on the risk-return matrix when compared with other debt schemes. There is considerable amount of research being done regarding investment in mutual funds. However very little research has been done to study the perception of investors regarding investment in mutual funds especially MIP funds. Literature Review Ippolito (1992) states that an investor is ready to invest in those fund or schemes which have resulted in good rewards and most investors’ are attracted by those funds or schemes that are performing better over the worst. Goetzman (1997) opined that investor’s psychology affects mutual fund selection for investment and to withdraw from the fund. De Bondt and Thaler (1985) submitted that mean reversion in prices of stock is backed by investor’s retrogression which is based upon investor’s psychology to overvalue firm’s recent performance in forming future expected results which is also known as endowment effect. Gupta (1994) surveyed household investor to find investors’ preferences to invest in mutual funds and other available financial assets. The findings of the study were more relevant, at that time, to the policy makers and mutual funds to design the financial products for the future. Kulshreshta (1994) in his study suggested some guidelines to the investors’ that can help them to select needed mutual fund schemes. Shanmugham (2000) conducted a survey of individual investors with the objective to find out what information source investor depends on. The results explained that they are economical, sociological and  psychological factors which control investment decisions. Madhusudhan V Jambodekar (1996) conducted his study to size-up the direction of mutual funds in investors and to identify factors that influence mutual fund investment decision. The study tells that open-ended scheme is most favored among other things and that income schemes and open-ended schemes are preferred over closed- ended and growth schemes. News papers are used as information source, safety of principal amount and investor services are priority points for investing in mutual funds. Sujit Sikidar and Amrit Pal Singh (1996) conducted a survey to peep in to the behavioral aspects of the investors of the North-Eastern region in direction of equity and mutual fund investment. The survey showed that because of tax benefits mutual funds are preferred by the salaried and self-employed individuals. UTI and SBI schemes were most preferred in that region of the country over any other fund and the other funds had been proved archaic during the time of survey. Syama Sunder (1998) conducted a survey with an objective to get an in-depth view into the operations of private sector mutual fund with special reference to Kothari Pioneer. The survey tells that knowledge about mutual fund concept was unsatisfactory during that time in small cities like Visakapatanam. It also suggested that agents can help to catalyse mutual fund culture, open-ended options are much popular than any other schemes, asset management company’s brand is chief consideration to invest in mutual fund. Anjan Chakarabarti and Harsh Rungta (2000) emphasised the importance  of brand in ascertaining competence of asset management companies. Shankar (1996) suggested that for penetrating mutual fund culture deep in to society asset management companies have to work and steer the consumer product distribution model. Raja Rajan (1997) underlined segmentation of investors and mutual fund products to increase popularity of mutual funds. Objectives of Study 1. To study the investment pattern of Indian Investor. 2. To find out the awareness level of investors regarding mutual funds. 3. To find the type of scheme of mutual fund preferred by investor. 4. To find out the importance of factors like liquidity, higher return, company reputation and other factors that influence investment decision of mutual fund holder. 5. To find out awareness level of investors regarding Monthly Income Plan fund. 6. To ascertain the most preferred factor for investing in MIP fund. Research Methodology Investor’s main objective is to earn higher returns keeping in mind the risk and liquidity factor. With this objective in mind, an investor is looking out for various investment avenues. Mutual funds offer comparatively better returns and have less risk as compared to direct investment in stock market. In this research paper, an attempt has been made to evaluate the perception of investors regarding mutual fund investment with special emphasis on Monthly Income Plan funds. A survey was conducted in Pune city during the period June 2013 to September 2013. A sample of 150 individual mutual fund investors were surveyed through a pre-tested questionnaire. The investors were selected on the basis of those who have made prior investment in mutual funds and have some knowledge about the basic terminologies involved with mutual funds. An attempt has been made to find out the perception of investors regarding mutual fund investment and to identify the factors considered to be important by the investors before investing in any mutual fund. The awareness level of investors regarding Monthly Income Plan funds and their benefits is also studied.