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

Review of a Leader Movie Armageddon Essay

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

Perception towards mutual funds Essay

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

Free Essays on Epicureanism And Stoicism

The Stoics and Epicureans date from the Hellenistic period (ca. 323 BC - 31 BC), and both schools were heavily influenced by the philosophy of Socrates. The Epicurean mission was to live virtuously in a wicked world. They advocated a simple, quiet, reclusive, sensible life of moderation among friends, avoiding extravagant worldly attractions and bringing no trouble on others. A wise person was one who exhibits rational self-control, subordinating excessive impulses and emotion-laden desires to the law of reason. The Epicureans were suspicious of overly artful or sophisticated intellectual debates; they preferred ordinary language and relied only on sense impressions to establish what we perceive or know. The Epicureans sought a life of pleasure that is, minimal pain and maximum peace of mind by rejecting external goods and pursuing true and lasting internal qualities such as justice, honor, and wisdom. Epicurus said there are four basic truths: (1) there are no divine beings to threaten us; (2) there is no next life; (3) the little we actually need is easy to get; and (4) what makes us suffer is easy to put up with. For the Stoics, logos was seen as the rational order of all things, as reflected in the three areas of philosophy: logic (knowledge, grammar, rhetoric, semantics), physics (cosmology, biology, geography, causality, psychology, theology), and ethics (the goals, proper functions, moral responsibility, and virtue of human character). Human virtue was seen as the highest pattern of a life that accords with universal nature. The early Stoics (Zeno, Cleanthes, Chrysippus) were brilliant practitioners of paradox and dialectic (i.e. debates involving fine logical distinctions); their ideal was the sage, who could refute or trump all others. The later Stoics (Seneca, Epictetus, and Marcus Aurelius) emphasized the ideal of a model virtuous citizen, who fulfills his or her highest nature (which for humans is reason).... Free Essays on Epicureanism And Stoicism Free Essays on Epicureanism And Stoicism The Stoics and Epicureans date from the Hellenistic period (ca. 323 BC - 31 BC), and both schools were heavily influenced by the philosophy of Socrates. The Epicurean mission was to live virtuously in a wicked world. They advocated a simple, quiet, reclusive, sensible life of moderation among friends, avoiding extravagant worldly attractions and bringing no trouble on others. A wise person was one who exhibits rational self-control, subordinating excessive impulses and emotion-laden desires to the law of reason. The Epicureans were suspicious of overly artful or sophisticated intellectual debates; they preferred ordinary language and relied only on sense impressions to establish what we perceive or know. The Epicureans sought a life of pleasure that is, minimal pain and maximum peace of mind by rejecting external goods and pursuing true and lasting internal qualities such as justice, honor, and wisdom. Epicurus said there are four basic truths: (1) there are no divine beings to threaten us; (2) there is no next life; (3) the little we actually need is easy to get; and (4) what makes us suffer is easy to put up with. For the Stoics, logos was seen as the rational order of all things, as reflected in the three areas of philosophy: logic (knowledge, grammar, rhetoric, semantics), physics (cosmology, biology, geography, causality, psychology, theology), and ethics (the goals, proper functions, moral responsibility, and virtue of human character). Human virtue was seen as the highest pattern of a life that accords with universal nature. The early Stoics (Zeno, Cleanthes, Chrysippus) were brilliant practitioners of paradox and dialectic (i.e. debates involving fine logical distinctions); their ideal was the sage, who could refute or trump all others. The later Stoics (Seneca, Epictetus, and Marcus Aurelius) emphasized the ideal of a model virtuous citizen, who fulfills his or her highest nature (which for humans is reason)....

Chinas Economic Prosperity †Economics Essay (200 Level Course)

Chinas Economic Prosperity – Economics Essay (200 Level Course) Free Online Research Papers China’s Economic Prosperity Economics Essay (200 Level Course) The article talks about china’s economic prosperity in terms of attracting manufacturing jobs and cheap labor. The claim that china is keeping its currency undervalued to attract foreign investment and to make investment costs down might be true. Since the 1990’s began, china has been able to attract more and more manufacturing jobs from the us especially consumer goods manufacturing (textiles, toys etc). With its undervalued currency, china is able to attract major manufacturing companies from the USA to trade in Textiles, Consumer Goods and other light goods. The undervaluation of china’s currency makes it easier for foreign investors to buy and setup manufacturing activities at a much lower cost compared to any western country. This has resulted in major job losses in the manufacturing sector especially in the us. Another issue is the trade deficit that the USA and china have. China is currently exporting more goods and services to the USA ($125 Billion) compared to $25 Billion being exported to china from the USA. The WTO should definitely step in order to make china trade practices more in line with the rest of the WTO member counties. Research Papers on China’s Economic Prosperity - Economics Essay (200 Level Course)Definition of Export QuotasRiordan Manufacturing Production PlanTwilight of the UAWPETSTEL analysis of IndiaInfluences of Socio-Economic Status of Married MalesBionic Assembly System: A New Concept of SelfMarketing of Lifeboy Soap A Unilever ProductAnalysis of Ebay Expanding into Asia19 Century Society: A Deeply Divided EraThe Effects of Illegal Immigration

Economy Essay Example | Topics and Well Written Essays - 750 words

Economy - Essay Example Thus, this chapter discusses both the supply-side and demand-side factors that lead to differences in occupations and earnings. The authors, based on statistical analysis, note here that occupational segregation has declined over the past 30-40 years as women increasingly aspire for better education and have become more competitive than before. They however warn that despite these latest trends, gender disparity continues to be noticeable among different occupations. For example, Women comprised over 95% of nurses and constituted over four-fifths of all schoolteachers during the mid-nineties. Men, on the other hand, were dominant in the manufacturing sector. Blau et al note that gender and wage differences have remained existent for long periods as both groups have restricted themselves to such specific professions. They further attribute gender differences as the primary reason for discrepancies in job hierarchies, promotions and pay and analyze these factors to highlight their indi vidual and collective impact on the male and female workforce. Chapter 6: Differences in Occupations and Earnings: The Human Capital Model This chapter introduces the role of various factors like educational attainment, productivity and training in narrowing the gap in pay based on gender differences. The authors contend that rising educational qualifications among women has resulted in subtle cracks in the glass ceiling that is apparent in most corporate organizations, and explain it using the Human Capital Model. The authors study the relationship between labor longevity and investment in higher education and argue that women tend to invest in the latter as they see better prospects for staying within the workforce for longer durations. They further noted that women prefer on-the-job training citing better employment prospects and as a way to reduce any potential barriers to career advancement. These trends reflect on declining barriers to career opportunities besides throwing lig ht on changing practices among educational institutions with regards to admission policies and inclusion of a higher percentage of women. The authors also cite several legislations such as the Title IX of 1972 as additional reasons for reduction in gender-based discrimination among educational establishments. For instance, the percentage of women in institutions of higher education has risen from a meager 7% during the 1960s to as much as 35-40% across all professional fields and courses of study. The authors also discuss in length about the ‘Index of Segregation’, which measures the extent of segregation on the basis of gender across several hundred occupations. Numerically, this index estimates the percentage of each sex who must change jobs in order for the professional distribution amongst the two groups to reach equilibrium. Over the years, the Index has reduced from a massive 67% (in terms of women) to nearly half by the turn of the century. Chapter 7: Differences in Occupations and Earnings: The Role of Labor Market Discrimination Through this chapter, the authors primary demonstrate that discrimination within the labor market does exist when two similar individuals with equal qualifications, experience and profiles are

Sustainable Urban Dynamics Term Paper Example | Topics and Well Written Essays - 1000 words

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