The drug metabolism

The dose metamorphosis incomingIf an exogenous microorganism inaugu aims the human personify, this invokes the immune system to heighten antibodies to come into contact with the foreign emfly pathogenic species and lead to its destruction. Although when dose particles enter the human body this does non resolving in the discount of antibodies, cod to their relatively low molecular weight. This is why the endogenous metabolism of medicates is vital in ensu teleph superstar no or the minimum noxiousity from a rattling unspecific spectrum of xenobiotics i.e. soupcons/ rises which ar show in a given organism, but be not synthesized naturally by it and or normally found inwardly it. We fuck define medicate metabolism as the enzymatically catalysed conversion of exogenous dose molecules into full world(a)ly little active metabolites, which redeem a faster rate of clearance from the body. ( temporary hookup this is true for the majority of metabolites it is im portant to hump that just near metabolites actually argon of amplyer toxicity than their precursors.) This occurs throughout climb uply every organ (excluding ectodermic tissue) in the human body, but specificizedally the gastro-intestinal tract, lungs, kidneys and or so importantly (and abundantly) the liver.While drug metabolism is all-important(a) in preventing a specific toxicity world take ond from the accumulation of a drug(s), there atomic number 18 drawbacks that bring to be addressed a given drug may be a xenobiotic, but it is realizen (or administered) in order to produce some degree of a curative effect for its specifically tar puted unsoundness/pathology. t wherefore drug metabolism evoke inhibit the therapeutic benefit of a given molecule that ideally needs to be retained in a particular tissue of the body for a set period of time, to bring about a therapeutic effect. This is mainly ascribable to the fact that a great(p) number of drug molecules d o mimic the structure of endogenous molecules close enough for the fit specific enzymes to stooge them as well as nonspecific enzymes which only identify trusted molecular classifys as opposed to the entire pharmacophore of a given drug. This unexpected drug metabolism could result in an undesired decrease in the bioavailability of a drug which would lead to ontogenesisd doses or dosold age frequencies this would stick a decrease in patient compliance which in the current medicinal environment is vital. engrossment and clearanceIn the case of drug absorption into the desired tissues of the body generally a oleophilic character is waitd. This is because regardless of the site of drug uptake, it must slide by through the cell membranes of targeted cells. These cell membranes be lipophilic in nature as they consist of a phospholipid bilayer. The inside of this bilayer is made up of hydrocarbon chase after which are straight chain hydrocarbons which interact with each some other via Van der Waal inter action at laws and London forces. Thus drug molecules are designed to bewilder sufficient lipophilic character that they can play these interactions with the lipid bilayers and get going into cells. Unfortunately this means that they are of limited hydrophilicity and either do not go into dissolution in an sedimentary environment at all or do so at a very slow rate. As previously menti adeptd as this is unaccept fitting due to the accumulation of a given drug that would occur and produce toxicity, the drug must undergo a series of trans organic laws that serve to increase the hydrophilic nature of the drug molecules. This predominately occurs in liver cells (hepatocytes) in processes known as soma I and phase II metabolism. sort I and Phase IIPhase I metabolism is constituted of oxidative, reductive and hydrolytic chemical reactions. These serve to produce base metabolites that are susceptible to other reactions, which consist of the following conj ugations glucuronic acid, sulphate, aminic acid, glutathione, water, acetyl, buttery acid and methyl. These occur via the corresponding conjugating agents and are known as phase II reactions. They aim to produce secondary metabolites that are far to a greater extent hydrophilic nature than their precursor drug counterparts. This is with the addition of e.g. amine, carboxyl acid, hydroxyl groups as well as others, simply to increase the number of very electronegative atoms (with lone(prenominal) partner offs of electrons) in a given species. Thus these metabolites can from a great number of hydrogen bonds with the aqueous medium of the nephronal filtrate of the kidneys and be excreted at a faster rate via the passing of urine.The main cistron of phase I trans institutions are oxidative reactions, as they activate the selected species in generally one of cardinal ways hydroxylation and epoxidation. We can define oxidation as the gain of oxygen in a molecule or more precisely t he loss of at least one electron from a species reacting with molecular oxygen. This is true for the two general mechanisms mentioned supra as adding either a hydroxyl group or an epoxide ring to a molecule increases the number of oxygen atoms that the molecule contains. Firstly this increases the ability of the newly organize metabolite to act as a nucleophile due to the lone pair of electrons available for covalent bond formation (from the oxygen atom added to the molecule). Secondly it increases the chances of attack by an electrophilic species, because of the high electron density of the lone pair of electrons on the oxygen atom.OxidationProperties and mechanisms of the Cytochrome P450 isoenzyme superfamilyThe majority of these oxidative metabolic reactions are carried out by a superfamily of enzymes known as cytochrome P450, this can be displayed asRH + O2 +NAD(P)H + H+ ? ROH + H2O + NAD(P)+ 1The P450 enzymes catalyse the biodegradation of other exogenous species that are not drugs much(prenominal) as organic solvents, ethanol (or consumed alcohol), anaesthetics, pesticides and carcinogens 1 While endogenous molecules such as organic acids, steroids and prostaglandins are also biodegraded 1. These enzymes are intracellular hemoproteins that map as external monooxygenases (mixed function oxidases) enzymes that serve to incorporate a single atom of molecular oxygen into a lipophilic xenobiotic substrate (i.e. a drug molecule), with the concomitant reducing of the other atom to water 1. While internal monooxygenases take two reductive equivalents from the substrate in order to decoct one atom of molecular oxygen to water, this is normally done with an external reductant for external monooxygenases 1.In eukaryotic cells the P450 enzymes consist of around half(a) a thousand amino acid that compose their quaternary structure, these hemoproteins are membrane climb up and have a heme prosthetic group at their centres. It is thought process that the reason the enzymes can be bound to the cell membranes is the N-terminus of the enzymes tertiary structure has numerous hydrophobic amino acids (i.e. ones which contain remindful/cyclic groups and have few very electronegative atoms such as oxygen and sulphur) that can interact with the lipid bilayer of the cells. just about hemoproteins in mammalian cells have nitrogen atom from the histidine residues imidazole group to form a ligand with the iron-heme prosthetic group. While for P450 enzymes this ligand is make amidst the prosthetic group and the thiol group of a cysteine residue which is located near the C-terminus of the protein. This ligand activates the porphyrin ring (four conjugated pyrrole rings) to nucleophilic substitution by an oxygen atom. This is because the thiol group has an electron inductive effect due to its high electronegativity and so makes the carbon atom it is directly bonded to very overconfident and thus of greater electrophilicity/susceptibility of nucleophi lic attack by the lone pair of electrons from the oxygen atom, so stomaching oxidation to take place.The general process of the catalytic oxidative cycle of the cytochrome P450 enzyme superfamilyThe substrate binds to a specific P450 enzyme and is followed by the basic electron of the coenzyme NADPH via the electron transport chain. This is then followed by the binding of an oxygen atom that accepts the second electron from the coenzyme to produce a ferric peroxy anion 1.The anion forms a ferric hydroperoxy complex via protonation, which in turn is heterolytically cleaved to form a Fe(V)=O species 1.The newly formed highly electrophilic iron-oxo ordinary then attacks the substrate to form a hydroxylated metabolite. This product disassociates to allow another substrate to bind and the oxidation cycle to continue 1.Schematic organisation of different cytochrome P450 systems. upper berth row, left bacterial system, right mitochondrial system. Lower row, left microsomal system, righ t self-sufficient CYP102 (P450-BM3).1 redolent(p) hydroxylationThis leads on to the beginning major constituent of oxidative reactions aromatic hydroxylation. This is simply the addition of at least one hydroxyl group to a given substrate although depending on the chemical environment that the product is formed in (e.g. pH) the hydrogen atom may be lost from the hydroxyl group. Aromatic compounds are first metabolized to the corresponding arene oxides this is by electrophilic addition of the aromatic ring (of the previously mentioned iron-oxo intermediate) to produce either a carbocation species. This carbocation would be formed via the movement of an electron to the Fe(IV) species, giving a Fe(III) species bound to a the mentioned carbocation or by formation of a radical which serves as a tetrahedral intermediate.The produced arene oxides then take on elevate transformations, which involve remotion of the epoxide group that was added and introduction of a hydroxyl group and potent ially another nucleophilic substitute. The simplest transformation is simply intramolecular rearrangement to for a para-arenol. Also hydration can take place in the presence of water and using the enzyme epoxide hydrolase. This causes outset of the epoxide ring and formation of a trans-3,4 arenediol. These primary metabolites can also undergo attack by large macromolecules which serve as nucleophiles. This is because the oxygen in the epoxide ring serves to make both the meta and para carbon positions electropositive and electrophilic in nature. Although every nucleophilic substitution that does go on to occur is at the para position, due to greater resonance stability of the formed secondary metabolite.Another mannikin of aromatic hydroxylation would be the metabolism of isoliquiritigenin. It is a chalcone found in licorice roots and other plants 3 which has shown potent antitumor, phytoestrogenic activity and antioxidant properties. 3 Schematics for its metabolism can be shown b elow. 3The metabolism of aromatic compounds that get hydroxylated can be slowed by using para-substituted aromatic compounds with either centiliter or a fluorine atom in the para position. While electron withdrawing groups deactivate the ring towards electrophilic substitution and activate it towards nucleophilic substitution electron donating groups activate the ring towards electrophilic substitution and deactivate it towards nucleophilic substitution. While most ring deactivators go in the meta position, halogens direct ortho-para, i.e. the same as ring activators. This is because the halogens, especially fluorine and centilitre are very electronegative and thus have an electron inductive effect and decrease the electron density of the ring. This inductivity is far greater than the resonance stability that the halogen can give the ring thus deactivating it. Thus the addition of these halogen atoms decreases the nucleophilic nature of the ring and decreases the rate of metabolis m. This can be shown with the metabolism of the drug Diclofenac (shown below 4) which is an anti-inflammatory drug as it is has a half-life of around one hour. While its derivative fenclofenac which has a para-substituted chlorine atom has a half-life twenty times longer.Alkene epoxidationEpoxidation of alkenes occurs readily, because they are more volatile than the ? bonds of aromatic compounds, this simply involves the addition of an epoxide ring to a molecule in order for it to then undergo further transformations. For exercising the drug Coumarin has been used clinically at high dosages in humans in the intervention of high-protein lymphedemas (Jamal and Casley-Smith, 1989) and as an antineoplastic agent in the treatment of renal cell carcinoma (Marshall et al., 1994) and malignant melanoma (Marshall et al., 1989). 5 It and its 3/7-hydroxy isomers undergo epoxidation and then either glutathione conjugation or non-enzymatic intramolecular rearrangement 5 to secondary metabo lites. This is shown schematically below. 5It is also vitally important that environmental carcinogens are broken down via drug metabolism, in particular by the P450 enzymes. For illustration acrylonitrile (AN2) is widely used in the production of acrylic and modacrylic fibres, plastics, rubbers, resins, and as a chemical intermediate in the synthesis of many other industrial products (IARC,1999). Early epidemiological studies have suggested that AN may increase the incidence of lung, colon, and stomach cancers among exposed workers (Thiess and Fleig, 1978 Blair et al., 1998).6 As a result P450 epoxidation is vital for preventing carcinogenic action of AN. While the metabolic basis of the acute toxicity of AN has not been fully elucidated, it is generally attributed to its metabolism to CEO (cyanoethylene oxide) and nitrile, and glutathione depletion. The primary target of acute toxicity of AN is the central nervous system due, at least partially, to the liberation of cyanide (Ahm ed and Patel, 1981 Benz et al., 1997). 6 The below diagram illustrates how AN is metabolised by the P450 enzymes, specifically the CYP2E1 isoform.6Alcohol and aldehyde metabolismAlcohols and aldehydes can be metabolized by cytochrome P450 enzymes to aldehydes and carboxyl acids respectively, but the majority of these transformations are catalysed by alcohol dehydrogenase and aldehyde dehydrogenase. These enzymes are predominantly in the liver and require the coenzyme NAD+ or NADP+. General equations for these reactions are shown below.Alcohol DehydrogenaseEz + RCH2OH + NAD + RCHO + NADH + H+Aldehyde DehydrogenaseEz + RCHO + NAD+ + H2O RCOOH + NADH + H+ReductionCytochrome P450 enzymes are used along with reductases to metabolise drugs that have a carbon atom that is able to be trim down such as a carbonyl or an unsaturated carbon, a nitro group or a compound with an azo group. In addition upon reaction usually a specific stereoisomer is formed. The structure of the rest of the compo unds often attribute to which stereoisomer is formed. few stereoisomers can prove to be toxic. carbonyl compoundsCarbonyl compounds are reduced by cytochrome P450 into alcohols and are NADP or NADPH dependent. The enzymes involved in the decrease of carbonyls are classified based upon their gene sequence, 3-D structure and cofactor dependence into superfamilies of medium-chain dehydrogenases/reductases, aldo-keto reductases, short-chain dehydrogenases/reductases which include carbonyl reductases. The majority of these enzymes are present in the cytosol however there are some that are found in the microsomes and mitochondria. Short-chain dehydrogenases/reductases (SDRs) and aldo-keto reductases (AKR) are the most common enzymes used in drug metabolism. These enzymes also exhibit high specificity for the drugs that they reduce.Saturated ketones reduced to alcohols whilst in an unsaturated ketone both the ketone group and the double bonds are both reduced. Steroidal drugs undergo oxi dation-reduction of the hydroxy/keto group at C177. This makes the compound more water soluble and hence easier to be excreted.Some metabolising enzymes behave differently and undergo different personas of reactions when in different cells. An example is carbonyl reductases within neoplasm cells and normal cells. These have become a target of new drugs such as oracin in the treatment of breast cancer 9. The enzymes within the cancer cells metabolise oracin and doxorubin more effectively than in normal cells hence reducing the efficacy of the cytostatic effect of the drugs.Some carbonyl compounds however do not undergo reduction via the cytochrome P450 pathway but are rather reduced by other pathways including the aldo-keto reductases (AKR). An example is a drug containing a 1,3-diketone derivative S-1360 which upon reduction produces a key metabolite HP1 which constitutes a major clearance pathway9.Nitrogen compoundsThe reduction of nitrogen containing compounds are reduced to amin es in order to aid excretion as amines are more water soluble than their nitro groups. Azo compounds on the other hand may be metabolised within the body to produce the active drug as opposed to the precursor which may be formulated to get pass the first pass effect or the hydrophilic barrier in order to enter their target cells. The azo group provides 2 compounds with amine groups which can be further metabolised like any other amine. Both of these functional groups are both reduced by cytochrome P450 enzymes and are NADPH dependent.HydrolysisThis is part of the Phase I metabolism pathway. The metabolites produced are all susceptible to Phase II conjugation and thus being excreted after the conjugation. The functional groups of the drugs that are metabolised by hydrolysis include esters and amides, which produce carboxyl acids, alcohols and amines. Esters are hydrolysed quicker than amides in vivo. foreign oxidation and reduction the reactions are typically not carried out by the cytochrome P450 system. The most of import enzymes involved in the hydrolysis of the esters and amides are carboxylesterases and arylesterases, cholinesterases and serine endopeptidases. The active site of the enzymes involved may be stereospecific as to which enantiomorph of the drug is metabolised and in addition which enantiomer of the drug is generated. Some of these products are toxic and dangerous to the body. aminic acid reactionsSeveral phase I reactions produce a carboxylic acid metabolite. Xenobiotic carboxylic acids can be metabolised before elimination by amino acid conjugation. Glycine the most common conjugating amino acid forms bonce conjugates that are water soluble with aromatic, arylaliphatic and heterocyclic carboxylic acids. In these reactions, first the xenobiotic carboxylic acid is activated by ATP to form the angstrom unit ester by the enzyme acyl synthetase. Then the AMP ester is converted to a Coenzyme-A thioester. Next, an amide or peptide bond is formed between the thioester and the amino group of glycine. The latter reaction is mediated by the enzyme acyl transferase. These reactions are shown in figure 1.The amino acid conjugate produced is ionic and so water soluble, hence it is easily eliminated in the urine and bile. (1)Glutathione conjugationGlutathione is a protective compound in the body that removes potentially toxic electrophilic compounds and xenobiotics. Drugs are metabolised by phase I reactions to form virile elecrophiles that can react with glutathione to form conjugates that are not toxic. This phase II reaction differs from others since electrophiles are effect to conjugations rather than nucleophiles. The nucleophilic thiol group on the glutathione compound (figure 2) attacks elecrophiles (electrophilic carbons with leaving groups).Compounds that can be conjugated to give thioether conjugates of glutathioneEpoxidesHaloalkanesNitroalkanesAlkenesAromatic halo- and nitro- compoundsGlutathione-S-transferases (GST) are enzymes which catalyse the reactions above. There are thirteen different human GST subunits which have been identified and they pop off to phoebe bird different classes. They are located in the cytosol of the liver, kidney and intestine. The enzyme GST is thought to increase the ionisation of the thiol group of glutathione, leading(p) to an increase in its nucleophilicity towards electrophiles. (1)(2)Once formed, GSH conjugates may be excreted directly or more often they are further metabolised to N-acetylcysteine conjugates which can then be excreted via phase III metabolism.Phase III Metabolism further modification and excretionBefore being excreted in the urine, most xenobiotics are made less toxic and more water soluble as polarity increases by metabolising enzymes in phase II reactions. In phase III metabolism water soluble compounds are excreted in the urine. However, some drug compounds are not metabolised and therefore are not excreted. These non-metabolised compou nds are readily reabsorbed from the urine through the renal tubelike membranes and into the plasma to be recirculated. (3)Some xenobiotic conjugates from phase II reactions are further metabolised during phase III metabolism reactions. Glutathione-S conjugates may be metabolised further by hydrolysis of the glutathione conjugate (GSR) at the y-glutamyl bond of the glutamate residues by y -glutamyl transferase (y -GT) followed by hydrolysis of glycine residues resulting in a cysteine conjugate containing a free amino group of the cysteine residue. This then undergoes N-acetylation to form mercapturic acid. The final products mercapturic acids are S-derivatives of N-acetylcysteine synthesised from glutathione (figure 4). (1)(2)First-pass MetabolismThe metabolism of many drugs is dependent on the route of administation therefore viva voce administered drugs are subject to first pass metabolism and consequently their bioavailablity is reduced. This occurs as a result of the orally ad ministered drugs entering the systemic circulation via the hepatic portal vein, so the drug is exposed to the intestinal wall and the liver, which is thought to be the main site of first-pass metabolism of orally administered drugs. Other possible sites are the gastrointestinal tract, line of business, vascular endothelium and lungs.First-pass Metabolism in the LiverDuring first-pass metabolism, the cytochrome P450 enzymes family represent the most significant of the hepatic enzymes. It has been estimated that the endoplasmic reticulum of the liver contains about 25 000 nmol of cytochrome P450. Although there are several human P450 subfamilies and multiple individual isozymes within subfamilies, only five P450 enzymes are shown to be significant for the process of first-pass metabolismCYP1A2CYP2C9CYP2C19CYP2D6CYP3A4Cytochrome P450 drug substrates are commonly highly extracted during first-pass metabolism. Examples of these drugs are morphine, verapamil, propranolol, midazolam, lid ocaine. Drugs that are highly extracted such as lidocaine have a low bioavailability when taken orally therefore they are not administered orally. CYP3A4 is the most commonly active isozyme against P450 drug substrates. This is possibly due to the enzymes abundance and broad substrate specificity. Highly extracted substrates for conjugative, reductive or non-P450 oxidative enzymes are less common. These include labetalol, morphine, terbutaline, isoproterenol and pentoxifylline.The gut is also an important organ involved in pre-systemic metabolism. Metabolism here for drugs with high first-pass metabolism leads to a reduced bioavailability. Some metabolizing enzymes such as CYP3A4 is found at a higher level in enterocytes than in the liver. Recent findings state that gut wall metabolism is the major cause of low bioavailability of certain drugs.Intestinal First-pass MetabolismVarious drug metabolizing enzymes found in the liver are also found within the epithelium of the gastrointest inal tract. These include cytochromes P450, glucuronosyl transferases, sulfotransferases, N-acetyl transferase, glutathione S-transferases, esterases, epoxide hydrolase and alcohol dehydrogenase. The small intestine contains high amounts of three cytochrome P450 enzymes CYP3A, CYP2D6 and CYP2C. Unlike the liver which has a relatively uniform distribution of P450enzymes, the distribution of P450 enzymes is not uniform along the small intestine and villi. Proximal mucosal P450 content is normally higher than distal mucosa P450 content.Therefore it has been constituted that protein level and catalytic activity of drug-metabolizing enzymes in the small intestine are generally lower than those in the liver. This has been demonstrated by comparison of cytochrome P450 enzymes in the liver and the small intestine. The extent of first-pass metabolism can result from interindividual variabilityGenetic variationInduction or inhibition of metabolic enzymesFood increases liver air flow. This c an increase the bioavailablity of some drugs by increasing the amount of drug presented to the liver to an amount that is above the threshold for complete hepatic extractionDrugs that increase liver blood flow (similar effects to food) and drugs that reduce liver blood flowNon- linear first pass kinetics, i.e. doseLiver disease increases the bioavailability of some drugs with extensive first-pass metabolism (4)To avoid first pass metabolism a drug can be administered sublingual and buccal routes. These routes lead to drugs being absorbed by the oral mucosa. During sublingual administration the drug is put under the tongue where it dissolves in salivary secretions. An example of a sublingual drug is nitroglycerine. During buccal administration the drug is positioned between the teeth and the mucous membrane of the cheek. Both of these routes avoid destruction by the GI fluids and first pass effect of the liver. Drugs may also be administered via other routes to avoid first-pass metab olism, for example rectal, inhalation, transdermal, intravenous. (5)ProdrugsMany drugs require metabolic activation in order to exert their pharmacological action these are described as pro-drugs. There are two types type I and type II which has subtypes A and B dependent on the site of activation. Type I prodrugs are converted intracellularly at the target cells (A) or at tissues that usually metabolise compounds (B). An example of a type IA prodrug is Zidovudine and type IB prodrug is captopril. metabolous activation of type I prodrugs is usually linked to phase I metabolic enzymes. Type II prodrugs are converted extracellularly in GI fluids (A) or in the systemic circulation (B). An example of a type IIA prodrug is sulfasalazine and type IIB prodrug is fosphenytoin. Type II prodrugs are very popular as they are involved in overcoming bioavailability problems, which are commonly experienced with many drugs, by improving permeability and reducing the first pass effect. (6)Type I Pr odrugs are used to target a drug to its specific site of action an example of this is the drug used in Parkinsons disease levodopa the inactive form of the drug which is metabolised in the neurone by the enzyme dopa decarboxylase to the active form dopamine. Dopamine does not cross the blood-brain barrier so it is given as the levodopa precursor which is lipophilic so it can cross the barrier and then metabolized in vivo to dopamine. (7)Another example of the use of prodrugs is the pharmacological activation of a type II prodrug Azathioprine to mercaptopurine which is a chemotherapeutic agent used in the treatment of leukaemia. When mercaptopurine is administered, its clinical usefulness is restricted because of its rapid biotransformation by xanthine oxidase to an inactive metabolite 6-thiouric acid. Therefore larger doses have to be given as it has a low bioavailability, this leads to toxicity. By administering mercaptopurine as its cysteine conjugate, the limitations can be over come. This ionic form of the pro-drug conjugate is selectively taken up by the renal organic anion transport system. The kidney B-lyase enzyme system then cleaves the prodrug conjugate to give the active mercaptopurine in the kidney (figure 5). (8)(9)To conclude, prodrugs can be metabolised in different ways to form the active drug. They can be used to target specific sites, improve absorption and improve oral delivery of poorly water-soluble drugs. They can also be used to avoid first pass metabolism in drugs with high first pass extraction and reduce toxicity. (6)Factors affecting metabolismThere are several factors that can affect drug metabolism. Age, sex, inducers and inhibitors are some of which can effect drug metabolism which are mentioned below.How does age affect drug metabolismThere are many physiological changes that occur with ageing. The changes have the potential to affect both drug disposition and metabolism. Drug metabolism is mainly functioned by the liver, its siz e, blood perfusion and synthetic capacity for proteins which all determine the rate of hepatic drug elimination5.Paediatric populationPhase one and phase two metabolic pathways may not be active at birth due to maturational changes. The paediatric population and elderly population have differences in their capacity to metabolise a drug which can therefore produce a lower or higher plasma submergence of active substances compared with adults depending on the enzyme system used. There are examples of metabolites produced by therapeutic agents in children that are not usually seen in adults. The metabolites produced maybe the reason for some of the efficacy and or toxicity visible with drug administration in children. An example is caffeine production in a neonate receiving Theophylline. Other therapeutic agents which show changes in metabolite production in children areValproic acid,paracetamol,Chloramphenicol,CimetidineSalicylamide.In most cases the differences that occur between ch ildren and adults are in the ratios of the metabolites relative to the parent drug rather than in new metabolites individual to the paediatric population with some exceptions. The paediatric population shows the same set of enzymes as the adult population. (1)In general age related changes in drug metabolism have been shown to occur due to a solvent of diminished enzyme activities within the elderly human liver due to the size of the liver decreasing and hepatic blood flow decreasing. With age the liver blood flow is generally reduced by about 20-30% and there is a decrease in liver size by about (17-36%).Currently there is no clear pattern however there are two general trends that crook the rate of metabolism. One trend is that drugs that are undergoing hepatic microsomal oxidation are more likely to be metabolised slowly in the elderly and those which are conjugated are not likely to be influence by the age factor. Secondly, drugs that have high hepatic clearance, extraction rat ios example-Chlormethiazole, and Labetalol and undergo extensive first pass metabolism whilst oral absorption may show a large increase in bioavailability in the elderly.Elderly populationIn general in the elderly population hepatic blood flow decreases up to 40% and there can be a considerable reduction in the amount of drug reaching the liver per unit. Studies have shown that the effect of ageing on liver enzymes with particular drug