Essay on Miss Havisham in Great Expectations - 2451 Words

In Great Expectations, Dickens depicts an eccentric character in Miss Havisham. The unmarried Miss Havisham seems to both conform to and deny the societal standards of unmarried women in the Victorian Age. Spinsters and old maids display particular attitudes and hold certain functions in the society. Miss Havishams character shows how one woman can both defy and strengthen these characteristics. She, along with several other female characters in the novel, supports the fact that unmarried women were growing in number. In addition, her extravagant appearance aligns her with the common misconceptions of a spinsters appearance as common and unattractive, as well as makes her outcast from society like many unmarried women were.†¦show more content†¦17). Miss Skiffins, Wemmicks friend, presents herself not only as a single woman but one who takes care of her own finances, which was uncommon in this day. And then there is Miss Havisham, who has risen to the status of o ld maid through the mere passage of time. All of these women provide examples from the text of single women, which supports the contention of the time that single women were growing in number. Although Biddy and Miss Skiffins do marry, it is important to note not only the length of their spinsterhood, but the circumstances under which it comes to an end. Biddy can only become Joes wife after Mrs. Joe dies. Wemmick waits until precisely the right time in his affairs to propose to Miss Skiffins so as not to disturb the natural order of his very structured life. While these single women offer a distinct presence in the novel, none plays a large role in society. Spinsters were often viewed as outcasts from society; there was no respect for a woman who could not marry. Miss Havisham definitely fits the mold of an outcast. After being abandoned at the altar, she decides to stop time in her home in an effort to block out the memory. She removes all natural light from her surroundings and becomes a recluse. She stops the clocks at twenty minutes to nine, the time of her abandonment. She monitors her visitors; only people she has requested or desires to see are admitted to Satis House. ForShow MoreRelated The Vengeful Miss Havisham - Great Expectations Essay867 Words   |  4 PagesThe Vengeful Miss Havisham - Great Expectations. In Great Expectations, by Charles Dickens, Miss Havisham is a complex character whose past remains a mystery. We know about her broken engagement, an event that changes her life forever. Miss Havisham desperately wants revenge, and Estella, her adopted daughter, is the perfect tool to carry out her motives. With her plan of revenge in mind, Miss Havisham deliberately raises Estella to avoid emotional attachment and treat those who love herRead MoreMiss Havisham and Magwitch from Great Expectations Essay1035 Words   |  5 Pagesrelationship between character and location in the case of Magwitch and the marshes; Miss Havisham and Satis House (chapters 1-19) Both the characters Miss Havisham and Magwitch are linked closely with their respective surroundings, as Dickens employs imagery and pathetic fallacy to illustrate this. Although many characters in Great Expectations reflect their environments, the relationship of Miss Havisham and Magwitch offer a particular contrast. The novel echoes many of Dickens’s own lifeRead MoreThe theme of isolation in Great Expectations through Miss Havisham.3108 Words   |  13 PagesQuestion: How does Dickens in his portrayal of Miss Havisham explore the theme of isolation? The oldest of eight children, Charles Dickens was born in Portsmouth in 1812. Dickens experienced a very traumatic childhood which included the ordeal of seeing two of his brother pass away. John Dickens, his father, worked as a clerk in the Navy Pay Office, due to his occupation, the Dickens family had to move a lot. Financial problems led to the imprisonment of John Dickens, who couldnt afford to lookRead MoreEssay about In Great Expectations, Is Miss Havisham crazy and/or evil?1327 Words   |  6 PagesIn Great Expectations, Is Miss Havisham crazy and/or evil? The mad,eccentric and incredibly peculiar Miss Havisham,a wealthy dowager who lives in an old, rotting mansion secluded from the outside world is certainly one of the most memorable creations in the book Great Expectations written by Charles Dickens. From the first introductory scene on encountering Miss Havisham’s character it is immediately clear that she is supposed to leave a lasting impression on the reader. Dickens usesRead MoreComparing the Characters of Magwitch and Miss Havisham in Great Expectations by Dickens917 Words   |  4 PagesComparing the Characters of Magwitch and Miss Havisham in Great Expectations by Dickens Miss Havisham is a bitter old woman. She wants to seek revenge on all men for the wrong that was done to her by one man. She lives in her clothes that she should have worn to her wedding and is surrounded by decaying things in a darkened room. Miss Havisham adopts a young girl Estella, whom she has planed to use her to seek revenge on all men. Miss Havisham is delighted in the way EstellaRead More Great Expectations - Miss Havisham and Abel Magwitch are Living through Others1084 Words   |  5 PagesGreat Expectations - Miss Havisham and Abel Magwitch are Living through Others In the work Great Expectations, by Charles Dickens, two characters live their lives through someone else. Miss Havisham and Abel Magwitch are both elderly and though someone else are able to obtain their goals that they are not able to complete themselves. Abel Magwitch lives his life through the protagonist Pip while Miss Havisham lives her life through the character Estella. Miss Havisham is an aged, mysteriousRead MoreCreating Tension Through the Presentation of Magwitch and Miss Havisham in Great Expectations1182 Words   |  5 PagesHow does Dickens create tension through his presentation of Magwitch and Miss Havisham in Great Expectations? Introduction ============ Great Expectations is about a young boy, Pip, who lives in a deprived town with his sister (Mrs Joe) and her husband (Mr Joe). Pip meets a fugitive, Magwitch and after meeting with this runaway he fears from his life. Pip is then summoned to go and play at Miss Havisham’s house. He then falls in love with Estella who chooses to ignore Pip, which makesRead MoreThe Presentation of Miss Havisham in Chapter 8 and in Chapter 49 of Great Expectations by Charles Dickens814 Words   |  4 PagesThe Presentation of Miss Havisham in Chapter 8 and in Chapter 49 of Great Expectations by Charles Dickens In chapter 8 of Great Expectations, the author, Charles Dickens, initially presents Miss Havisham through Pips eyes as an eccentric old lady her hair was white, who lives in seclusion with her adopted daughter, Estella. She lives vicariously through Estella, all her inner thoughts and feelings are brought to life through Estella; therefore she is able to teach herRead MoreSymbolic References in Great Expectations by Charles Dickens1017 Words   |  5 PagesSatis House, the home of the wealthy dowager Miss Havisham, who is extremely eccentric: she wears an old wedding dress everywhere she goes and keeps all the clocks in her house stopped at the same time. During his visit, he meets a beautiful young girl named Estella, who treats him coldly and contemptuously. Nevertheless, he falls in love with her and dreams of becoming a wealthy gentleman so that he might be worthy of her. He even hopes that Miss Havisham intends to make him a gentleman and marryRead MoreGreat Expectations Prosperity Essay1598 Words   |  7 PagesHow are wealth and prosperity presented in Great Expectations? Dickens’ bildungsroman: Great Expectations dictates the life of a fortunate young gentleman who goes by the name of Pip, formally known as Philip Pirrip. Pip was born with only one relative to his name: Mrs. Joe, as she is referred to in the book. The book, typical of a bildungsroman, follows the protagonist -Pip- along his journey; originating from a relatively poor background and progressing to a more prosperous and wealthy future.

Drug Abuse in the United States on the Rise Essay - 634 Words

Drug Abuse in the United States has gone down since the 1990’s but now that percentage is starting to increase. Nowadays children perceive drugs to be less and less harmful and are deciding to try hard drugs such as amphetamines, stimulants, and opiates. These drugs are extremely addictive, one try and you could be hooked on for life. This is dangerous, the earlier children start to try drugs the more prone they are to dealing with addiction as adults. Drug abuse is a serious problem especially with America’s youth since marijuana and other drugs are very harmful to the developing brains of adolescents. Some of the most commonly abused drugs are Marijuana, Cocaine, Xanax, and Adderall. (Health and Life) Some of these drugs are more harmful†¦show more content†¦If a lot of kids start using drugs, the other kids who stay clean may feel pressured to fit in, people who use drugs may suggest for their friends to try it and create more drug abusers. Many people who use drugs try it to cope with stress or anxiety, but after the effect of the drugs wear off they may feel much worse than before. Helping people find healthy ways to deal with stress may be one way to reduce the amount of drug addicts. (Butler Center for Research) Another thing to be aware of is a family history of substance abuse, you might try drugs with friends and feel addicted to the drug after the first use your friend might be perfectly fine. Also persuading the youth to stay away from drugs is a key in prevention. â€Å"Research indicates that adolescence who begin drinking or doing drugs before age 14 are significantly more likely to experience alcohol or drug dependence at some point later on in their lives compared to individuals who begin drinking after 21 years of age.† (Butler Center for Research) Strong family bonds and proactive parenting can play a big role in helping keep teens away from drugs and alcohol. Everyone can do something to help prevent this issue. Friends could advise and put positive peer pressure on their friends to get them to not abuse drugs or even try them in the first place. Parents and adults canShow MoreRelatedSubstance Abuse Among Teenagers : A Survey1201 Words   |  5 PagesSubstance Abuse Among Teenagers Hannah is a fifteen year old girl who was recently sent to a rehabilitation center for the result of abuse of prescription medication. 6.1 million high school students currently use addictive substances, and like Hannah, 1 in 3 of them are addicted (â€Å"National Study Reveals,†2011). Although the number of teens using these drugs are decreasing, the numbers are still dangerously high. Due to it’s high risk of addiction, dangerous consequences, and growing availabilityRead MorePrescription Opioid Abuse : An Increasing Epidemic With Solutions945 Words   |  4 Pages Prescription Opioid Abuse: An Increasing Epidemic with Solutions in Prescribing The rate of poisonings associated with drug overdoses has been on the rise, especially concerning those involving opioids (Paulozzie, Budnitz, Xi, 2006). The Centers for Disease Control and Prevention (CDC) does not mince words regarding the status of opioid utilization in the United States: ?The United States is in the midst of an opioid overdose epidemic? (CDC, 2016). Opioids are now the most common cause of prescriptionRead MoreEconomic Impacts Of Drug Abuse1013 Words   |  5 PagesEconomic Impacts of Drug Abuse in the United States Drug abuse is a major public health issue that impacts society both directly and indirectly; every person, every community is somehow affected by drug abuse and addiction and this economic burden is not exclusive to those who use substance, it inevitably impacts those who don t. Drugs impact our society in various ways including but not limited to lost earnings, health care expenditures, costs associated with crime, accidents, and deaths. The useRead MoreSharing For Generic Abuse Analgesic Opioid Analgesic Drug Product And Require Medicaid Services Essay914 Words   |  4 Pagessharing for generic abuse-deterrent opioid analgesic drug product and require Medicaid services or a managed care organization to be compliant with the new sections to the bill ( Kentucky.gov, 2015). Bill #HB 330(BR-990) was filed and introduced into committee on Tuesday February 2nd, 2016 and sponsored by Addia Wuchner, Joni Jenkins, Linda Belcher, Regina Bunch, Kelly Flood, Kim King, Martha Jane King, Mary Lou Marzian, Donna Mayfield, Marie Rader, Rita Smart, Diane St. Onge, Susan Westrom and JillRead More Should Drugs Be Made Legal? Essay697 Words   |  3 PagesShould Drugs Be Made Legal? For several decades drugs have been one of the major problems of society. There have been escalating costs spent on the war against drugs and countless dollars spent on rehabilitation, but the problem still exists. Not only has the drug problem increased but drug related problems are on the rise. Drug abuse is a killer in our country. Some are born addicts(crack babies), while others become users. The result of drug abuse is thousands of addicts in denial. The goodRead MoreDecriminalization Of Drug Usage Among Portugal1299 Words   |  6 Pages Decriminalization of Drug Usage in Portugal Derrick Routon American Government 101 Professor Newman 21 April 2016  Portugal has garnered a large amount of attention since adopting a new method to combat drug usage. They have moved to decriminalize low scale drug possession and usage instead of an incarceration of low level offenders. Many nations have desired to reevaluate their own regimen of substance control and the way abuses were handled. The Portuguese governmentRead MorePrescription Opioid Abuse And Its Effects On Heroin Use Essay1550 Words   |  7 PagesNonmedical Prescription-Opioid abuse in the United States and Michigan has continued to rise, and with it, the devastating results that accompany it. Research has shown that increased opioid abuse leads to an increase in overdose and death, increases in crime and increased incidences of costly blood borne diseases like HIV, AIDS and Hepatitis. It also leads to increased societal costs, such as an increasing number of children in foster care and increased healthcare, workplace and criminal justiceRead MoreWhat Is The Total Economic Burd en Of Prescription Opioid Abuse?1662 Words   |  7 Pages2 â€Å"The total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year, including the costs of healthcare, lost productivity, addiction treatment, and criminal justice involvement†. -The Centers for Disease Control and Prevention Substance abuse disorders have been considered a major epidemic by public health authorities during this century. Most recently, those who use, and abuse opioids have been in the spotlight. The growing number of overdoses, deathsRead MoreThe Effects Of Drug Abuse On Society Essay1136 Words   |  5 Pagesall felt the effects of drug abuse. In other words, whether it affects an individual directly or indirectly every person has seen or felt the negative effects of drug abuse in our society. The ultimate question, is why does such an abounding amount of Americans abuse illicit drugs, and how does it affect us as a nation? Moreover, something such as this doesn t occur for without a distinct cause, there must be something occurring in our society that creates these illicit drug abusers. CorrespondinglyRead MoreDrug Abuse Effects1320 Words   |  6 PagesDrug abuse is a major public health issue that impacts society both directly and indirectly; every person, every community is someh ow affected by drug abuse and addiction and this economic burden is not exclusive to those who use substance, it inevitably impacts those who dont. Drugs impact our society in various ways including but not limited to lost earnings, health care expenditures, costs associated with crime, accidents, and deaths. The use of licit or illicit drugs long term, causes millions

Ethical decision issues in an Organization- Samples for Students

Question: Discuss about the Ethical decision issues in an Organization. Answer: There are several multinational organizations which have faced various ethical issues while taking their business decisions. It has been evaluated that with the increasing ramification of economic changes key managerial persons in business are more inclined towards taking their business decisions which are more profitable and taken for the best interest of the organization at large irrespective of the ethical issues. However, some business decision cannot successfully explain via individual traits because of behavior of free will (Pettey, 2013). Each and every organization has to consider business ethics while taking their business decisions. This could be defined with the example that Australian company Wesfarmers plc made investment of 10 million for promoting non charitable organizations for discharging its corporate social responsibilities. However, these acts have not resulted into higher cost of production of organizations which is not profitable nor provide any kind of benefit s to organizations (Shapiro, Stefkovich and Gutierrez, 2014). Therefore, in context with the business, decision taken by Wesfarmers is not profitable for the organization but as per the ethical business terms, Wesfarmers Ltd has taken ethical decision by investing its money in non charitable funds for promoting social and environmental acts. However, there are other several cases which are faced by organizations which are somehow legal but not ethical. For instance, testing products on animals, selling landmines to oppressive regimes which are legally acceptable but as per the ethical term these things are strictly prohibited in business. There are several situations in which it becomes hard to determine what is wrong and what is right. For instance, when an organizations is facing drastic loss in its business functions due to sluggish market conditions it goes for divestment or retrenchment strategies. However, retrenchment of employees is valid as per the laws and business interes t but in ethical term it becomes wrong. Employees who have given their lives in the best interest of organizations could not be fired on the basis of cost cutting strategies by the organizations. This business ethics decision could also be determined by using contract law example. For instance If an organization has entered into contract with the other organizations for delivering of some goods and service on stipulated date and due to some avoidable reason, that other organizations failed to perform its promise then in that case first organizations could sue that other organizations and can ask for compensation (Yeager, 2015). However, as per the legal law, it is valid act but if ethical consideration is taken into account then in that case, first organization could wait for some day and can allow other party to perform its promise. Sometimes these ethical business decisions are influenced by the individual and situational factors. These both factors help decision makers to determine the ethical factors of the particular situations. There are several theories such as descriptive theory, normative theory which helps businessman to determine the ethical issues and dilemma of the case while taking business decisions. It is important to determine the importance of differences in individuals in shaping ethical business decision. Therefore, it is required to evaluate all the internal and external factors of the persons who are going to get affected by the business decisions for the effective level of business decision in organizations. there are several limitation of ethical business decision in organizations such as it decrease the productivity of process system, increase the complexity of business decision, increase in overall cost, create business decision process long and result to cultural bias while overcoming the ethical issues with different level of stakeholders. For instant, employees in the organizations comes from different culture and countries, therefore taking business decisions to set up organizational cultural policies and laws may result to influenced the employees who have different level of culture in organization (Thome, and Ferrell, 2015). These individual factors of employees explain the reason why some people may be more swayed tha n other into unethical business conducts. Now in the end it would be inferred that each and every key managerial persons should take into account all the ethical factors while taking business decisions. If they fail to manage their ethical factors while taking business decisions then in short term they might create value on their business decisions but in future it will destruct the brand image of company and result to non effective business functioning of organizations (Shapiro and Stefkovich, 2016). References Pettey, J.G., (2013). Ethical Decision Making.Nonprofit Fundraising Strategy: A Guide to Ethical Decision Making and Regulation for Nonprofit Organizations, pp.245-253. Shapiro, J.P. Stefkovich, J.A., (2016).Ethical leadership and decision making in education: Applying theoretical perspectives to complex dilemmas. Routledge. Shapiro, J.P., Stefkovich, J.A. Gutierrez, K.J., (2014). Ethical decision making.Handbook of Ethical Educational Leadership, pp.210-228. Thome, D.M. Ferrell, O.C., (2015). Antecedents of Ethical Decision Making in Sales Organizations. InProceedings of the 1992 Academy of Marketing Science (AMS) Annual Conference(pp. 356-360). Springer International Publishing. Yeager, A.L., (2015). Ethical decision making.The Journal of the American Dental Association,146(8), pp.568-569.

The Gods Views In The Iliad Essays - Trojans, Mythological Kings

The Gods Views In The Iliad With our view of God, it can sometimes be difficult to comprehend the actions and thinking of the Greek deities. The Christian God does not tend to take such an active role in the affairs of people's lives, where, on the other hand, the Greeks regarded direct involvement by the gods as a daily, uncontrollable part of life. Needless to say, divine intervention was a major variable in the equation of Homer's Iliad. The gods picked whom they would favor for different reasons. Except Zeus: As the symbol of supreme authority and justice, he makes judgement calls as to the other gods' involvement in the war, remains impartial, and doesn't seem to get caught up in picking favorites. Even when his own son, Sarpedon, was about to die, Zeus chose to let the outcome go unaltered. On the other hand, Zeus's wife, Hera, displayed the more typical actions of a god. After Paris, a Trojan, judged Aphrodite the fairest over Hera, and, after her daughter Hebe was replaced as cupbearer to the gods by a young Trojan boy, she was quite resentful towards Troy and its people. Obviously she sided with the Greeks and would stop at no length to express her will. Scheming and manipulating she even dared to trick her husband, King of the Gods. Hera, along with Athena, who was also passed over by Paris, is seen as the chief divine aid to the Greeks. Being the god of the sea, Poseidon was another strong supporter of the ocean-faring Greeks. Whenever Zeus turned his back Poseidon tried to help the Greeks in the fight. Poseidon felt that he was somewhat Zeus's equal as his brother, but recognizing Zeus's authority and experience, he looked to Zeus as an elder. There were also Gods who favored the Trojan side of the conflict. Apollo and Artemis, twin brother and sister gave aid to the city of Troy. Although Artemis takes a rather minor role, Apollo perhaps angered by Agamemnon's refusal to ransom Chryseis, the daughter of one of his priests and was constantly changing the course of the war in f avor of the Trojans. Responsible for sending plague to the Greeks, Apollo was the first god to make an appearance in the Iliad. Also, mainly because Apollo and Artemis were on the Trojan side, their mother, Leto, also helped the Trojans. Aphrodite, obviously supporting Paris's judgement, sided with the Trojans. Although she was insignificant on the battlefield, Aphrodite was successful in convincing Ares, her lover and the god of war, to help the Trojans. One view of the gods' seemingly constant intervention in the war was that they were just setting fate back on the right course. For instance, when Patroclus was killed outside of Troy, Apollo felt no guilt for his doings. It had already been decided that Patroclus would not take Troy, he should never have disobeyed Achilles in the first place. As a god, he was just setting fate on a straight line. Achilles laid blame on Hector and the Trojans. He did not even consider accusing Apollo, who never came into question, although he was p rimarily responsible for the kill. Apollo's part in the matter was merely accepted as a natural disaster or illness would be today. This general acceptance of a god's will is a recurring trend throughout the poem. A prime example of this trend is in book XXIV. Achilles, angry over the death of Patroclus, brutally disgraced Hectors body. Tethering Hectors corpse through the ankles, Achilles dragged him around Patroclus tomb every day for twelve days. This barbaric treatment was uncalled for and displeased the gods greatly. Achilles mother, Thetis, was sent by Zeus to tell him to ransom the body back to the Trojans. One may think Achilles would be possessive of the body and attempt to put up a fuss as he did before with Agamemnon in Book I. Achilles showed humility and respect for the gods and immediately agreed to ransom the body to the Trojans, showing that all mortals, even god-like Achilles, were answerable to the gods. This ideology would seem to give the gods a sort of unlimited freedom on earth; although, the gods

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

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.

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

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,

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

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