The drug metabolism


If an exogenic micro-organism enters the human organic structure, this invokes the immune system to bring forth antibodies to come into contact with the foreign potentially infective species and lead to its devastation. Although when drug molecules enter the human organic structure this does non ensue in the synthesis of antibodies, due to their comparatively little molecular weight. This is why the endogenous metamorphosis of drugs is critical in guaranting no or the minimal toxicity from a really wide spectrum of xenobiotics i.e. molecules/compounds which are found in a given being, but are non synthesized of course by it and or usually found within it. We can specify drug metamorphosis as the enzymatically catalysed transition of exogenic drug molecules into by and large less active metabolites, which have a faster rate of clearance from the organic structure. ( While this is true for the bulk of metabolites it is of import to admit that some metabolites really are of higher toxicity than their precursors. ) This occurs throughout about every organ ( excepting ectodermic tissue ) in the human organic structure, but specifically the gastro-intestinal piece of land, lungs, kidneys and most significantly ( and copiously ) the liver.

While drug metamorphosis is indispensable in forestalling a specific toxicity being produced from the accretion of a drug ( s ) , there are drawbacks that need to be addressed ; a given drug may be a xenobiotic, but it is taken ( or administered ) in order to bring forth some grade of a curative consequence for its specifically targeted disease/pathology. Therefore drug metamorphosis can suppress the curative benefit of a given molecule that ideally needs to be retained in a peculiar tissue of the organic structure for a fit period of clip, to convey about a curative consequence. This is chiefly due to the fact that a big figure of drug molecules do mime the construction of endogenous molecules near plenty for the corresponding specific enzymes to aim them every bit good as nonspecific enzymes which merely identify certain molecular groups as opposed to the full pharmacophore of a given drug. This unexpected drug metamorphosis could ensue in an unsought lessening in the bioavailability of a drug which would take to increased doses or dose frequences ; this would do a lessening in patient conformity which in the current medicative environment is critical.

Absorption and clearance:

In the instance of drug soaking up into the coveted tissues of the organic structure by and large a lipotropic character is required. This is because regardless of the site of drug consumption, it must go through through the cell membranes of targeted cells. These cell membranes are lipotropic in nature as they consist of a phospholipid bilayer. The interior of this bilayer is made up of hydrocarbon dress suits which are consecutive concatenation hydrocarbons which interact with each other via Van der Waal interactions and London forces. Therefore drug molecules are designed to hold sufficient lipotropic character that they can organize these interactions with the lipid bilayers and base on balls into cells. Unfortunately this means that they are of limited hydrophilicity and either make non travel into disintegration in an aqueous environment at all or make so at a really slow rate. As antecedently mentioned as this is unacceptable due to the accretion of a given drug that would happen and bring forth toxicity, the drug must undergo a series of transmutations that serve to increase the hydrophilic nature of the drug molecules. This predominately occurs in liver cells ( hepatocytes ) in procedures known as stage I and phase II metamorphosis.

Phase I and Phase II:

Phase I metabolism is constituted of oxidative, reductive and hydrolytic reactions. These serve to bring forth primary metabolites that are susceptible to other reactions, which consist of the undermentioned junctions ; glucuronic acid, sulfate, amino acid, glutathione, H2O, ethanoyl group, fatty acid and methyl. These occur via the corresponding conjugating agents and are known as stage II reactions. They aim to bring forth secondary metabolites that are far more hydrophilic nature than their precursor drug opposite numbers. This is with the add-on of e.g. aminoalkane, carboxylic acid, hydroxyl groups every bit good as others, merely to increase the figure of really negatively charged atoms ( with lone braces of negatrons ) in a given species. Thus these metabolites can from a greater figure 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 piss.

The chief component of stage I transmutations are oxidative reactions, as they activate the selected species in by and large one of two ways ; hydroxylation and epoxidation. We can specify oxidization as the addition of O in a molecule or more exactly the loss of at least one negatron from a species responding with molecular O. This is true for the two general mechanisms mentioned above as adding either a hydroxyl group or an epoxide ring to a molecule increases the figure of O atoms that the molecule contains. First this increases the ability of the freshly formed metabolite to move as a nucleophile due to the lone brace of negatrons available for covalent bond formation ( from the O atom added to the molecule ) . Second it increases the opportunities of onslaught by an electrophilic species, because of the high negatron denseness of the lone brace of negatrons on the O atom.


Properties and mechanisms of the Cytochrome P450 isoenzyme superfamily:

The bulk of these oxidative metabolic reactions are carried out by a superfamily of enzymes known as cytochrome P450, this can be displayed as:

RH + O2 +NAD ( P ) H + H+ ? ROH + H2O + NAD ( P ) + [ 1 ]

The P450 enzymes catalyse the biodegradation of other exogenic species that are non drugs such as ; organic dissolvers, ethyl alcohol ( or consumed intoxicant ) , anesthetics, pesticides and carcinogens [ 1 ] ; While endogenous molecules such as organic acids, steroids and prostaglandins are besides biodegraded [ 1 ] . These enzymes are intracellular haemoproteins that function as external monooxygenases ( assorted map oxidases ) enzymes that service to integrate a individual atom of molecular O into a lipotropic xenobiotic substrate ( i.e. a drug molecule ) , with the attendant decrease of the other atom to H2O [ 1 ] . While internal monooxygenases take two reductive equivalents from the substrate in order to cut down one atom of molecular O to H2O, this is usually done with an external reducing agent for external monooxygenases [ 1 ] . In eucaryotic cells the P450 enzymes consist of around half a 1000 amino acid that compose their quaternate construction, these haemoproteins are membrane edge and have a heme prosthetic group at their Centres. It is thought that the ground the enzymes can be bound to the cell membranes is the N-terminus of the enzymes third construction has legion hydrophobic aminic acids ( i.e. 1s which contain aromatic/cyclic groups and have few really negatively charged atoms such as O and sulfur ) that can interact with the lipid bilayer of the cells. Most haemoproteins in mammalian cells have nitrogen atom from the histidine residues imidazole group to organize a ligand with the iron-heme prosthetic group. While for P450 enzymes this ligand is formed between 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 permutation by an O atom. This is because the thiol group has an negatron inductive consequence due to its high electronegativity and so makes the C atom it is straight bonded to really positively charged and therefore of greater electrophilicity/susceptibility of nucleophilic onslaught by the lone brace of negatrons from the O atom, so leting oxidization to take topographic point.

The general procedure of the catalytic oxidative rhythm of the cytochrome P450 enzyme superfamily:

  1. The substrate binds to a specific P450 enzyme and is followed by the first negatron of the coenzyme NADPH via the negatron conveyance concatenation. This is so followed by the binding of an O atom that accepts the 2nd negatron from the coenzyme to bring forth a ferrous peroxy anion [ 1 ] .
  2. The anion forms a ferrous hydroperoxy composite via protonation, which in bend is heterolytically cleaved to organize a Fe ( V ) =O species [ 1 ] .
  3. The freshly formed extremely electrophilic iron-oxo intermediate so attacks the substrate to organize a hydroxylated metabolite. This merchandise disassociates to let another substrate to adhere and the oxidization rhythm to go on [ 1 ] .

“ Conventional administration of different cytochrome P450 systems. Upper row, left: bacterial system, right: mitochondrial system. Lower row, left: microsomal system, right: self-sufficing CYP102 ( P450-BM3 ) . “ [ 1 ]

Aromatic hydroxylation:

This leads on to the first major component of oxidative reactions ; aromatic hydroxylation. This is merely the add-on of at least one hydroxyl group to a given substrate although depending on the chemical environment that the merchandise is formed in ( e.g. pH ) the H atom may be lost from the hydroxyl group. Aromatic compounds are first metabolized to the corresponding arene oxides ; this is by electrophilic add-on of the aromatic ring ( of the antecedently mentioned iron-oxo intermediate ) to bring forth either a carbocation species. This carbocation would be formed via the motion of an negatron to the Fe ( IV ) species, giving a Fe ( III ) species bound to a the mentioned carbocation ; or by formation of a extremist which serves as a tetrahedral intermediate.

The produced arene oxides so take on farther transmutations, which involve remotion of the epoxide group that was added and debut of a hydroxyl group and potentially another nucleophilic replacement. The simplest transmutation is merely intramolecular rearrangement to for a para-arenol. Besides hydration can take topographic point in the presence of H2O and utilizing the enzyme epoxide hydrolase. This causes gap of the epoxide ring and formation of a trans-3,4 arenediol. These primary metabolites can besides undergo onslaught by big supermolecules which serve as nucleophiles. This is because the O in the epoxide ring serves to do both the meta and para C places electropositive and electrophilic in nature. Although any nucleophilic permutation that does travel on to happen is at the parity place, due to greater resonance stableness of the formed secondary metabolite.

Another illustration of aromatic hydroxylation would be the metamorphosis of isoliquiritigenin. It is a chalcone found in licorice roots and other workss [ 3 ] which has shown powerful antitumor, phytoestrogenic activity and antioxidant belongingss. [ 3 ] Schematics for its metamorphosis can be shown below. [ 3 ]

The metamorphosis of aromatic compounds that get hydroxylated can be slowed by utilizing para-substituted aromatic compounds with either Cl or a fluorine atom in the para place. While negatron retreating groups deactivate the ring towards electrophilic permutation and trip it towards nucleophilic permutation ; electron donating groups activate the ring towards electrophilic permutation and deactivate it towards nucleophilic permutation. While most ring deactivators go in the meta place, halogens direct ortho-para, i.e. the same as pealing activators. This is because the halogens, particularly fluorine and Cl are really negatively charged and therefore hold an negatron inductive consequence and diminish the negatron denseness of the ring. This inductivity is far greater than the resonance stableness that the halogen can give the ring therefore deactivating it. Thus the add-on of these halogen atoms decreases the nucleophilic nature of the ring and decreases the rate of metamorphosis. This can be shown with the metamorphosis of the drug Diclofenac ( shown below [ 4 ] ) which is an anti-inflammatory drug as it is has a half life of around one hr. While its derivative fenclofenac which has a para-substituted Cl atom has a half-life 20 times longer.

Alkene epoxidation:

Epoxidation of olefines occurs readily, because they are more volatile than the? bonds of aromatic compounds, this merely involves the add-on of an epoxide ring to a molecule in order for it to so undergo farther transmutations. “ For illustration the drug Coumarin has been used clinically at high doses in worlds in the intervention of high-protein lymphedemas ( Jamal and Casley-Smith, 1989 ) and as an anticancer agent in the intervention of nephritic cell carcinoma ( Marshall et al. , 1994 ) and malignant melanoma ( Marshall et al. , 1989 ) . ” [ 5 ] It and its 3/7-hydroxy isomers undergo epoxidation and so either glutathione junction or non-enzymatic intramolecular rearrangement [ 5 ] to secondary metabolites. This is shown schematically below. [ 5 ]

It is besides vitally of import that environmental carcinogens are broken down via drug metamorphosis, in peculiar by the P450 enzymes. For illustration propenonitrile ( AN2 ) “ is widely used in the production of acrylic and modacrylic fibers, plastics, gum elastics, rosins, and as a chemical intermediate in the synthesis of many other industrial merchandises ( IARC,1999 ) . Early epidemiological surveies have suggested that AN may increase the incidence of lung, colon, and tummy malignant neoplastic diseases among open workers ( Thiess and Fleig, 1978 ; Blair et al. , 1998 ) . “ [ 6 ] As a consequence P450 epoxidation is critical for forestalling carcinogenic action of AN. While the “ metabolic footing of the acute toxicity of AN has non been to the full elucidated, it is by and large attributed to its metamorphosis to CEO ( cyanoethylene oxide ) and nitrile, and glutathione depletion. The primary mark of acute toxicity of AN is the cardinal nervous system due, at least partly, to the release of nitrile ( Ahmed and Patel, 1981 ; Benz et al. , 1997 ) . ” [ 6 ] The below diagram illustrates how AN is metabolised by the P450 enzymes, specifically the CYP2E1 isoform. [ 6 ]

Alcohol and aldehyde metamorphosis:

Alcohols and aldehydes can be metabolized by cytochrome P450 enzymes to aldehydes and carboxylic acids severally, but the bulk of these transmutations are catalysed by intoxicant dehydrogenase and aldehyde dehydrogenase. These enzymes are preponderantly in the liver and necessitate the coenzyme NAD+ or NADP+ . General equations for these reactions are shown below.

[ Alcohol Dehydrogenase ] Ez + RCH2OH + NAD + RCHO + NADH + H+

[ Aldehyde Dehydrogenase ] Ez + RCHO + NAD+ + H2O RCOOH + NADH + H+


Cytochrome P450 enzymes are used along with reductases to metabolize drugs that have a C atom that is able to be reduced such as a carbonyl or an unsaturated C, a nitro group or a compound with an azo group. In add-on upon reaction normally a specific stereoisomer is formed. The construction of the remainder of the compounds frequently attribute to which stereoisomer is formed. Some stereoisomers can turn out to be toxic.

Carbonyl compounds:

Carbonyl compounds are reduced by cytochrome P450 into intoxicants and are NADP or NADPH dependant. The enzymes involved in the decrease of carbonyls are classified based upon their cistron sequence, 3-D construction and cofactor dependance into superfamilies of ; medium-chain dehydrogenases/reductases, aldo-keto reductases, short-chain dehydrogenases/reductases which include carbonyl reductases. The bulk of these enzymes are present in the cytosol nevertheless there are some that are found in the microsomes and chondriosomes. Short-chain dehydrogenases/reductases ( SDRs ) and aldo-keto reductases ( AKR ) are the most common enzymes used in drug metamorphosis. These enzymes besides exhibit high specificity for the drugs that they cut down.

Saturated ketones reduced to alcohols whilst in an unsaturated ketone both the ketone group and the dual bonds are both reduced. Steroidal drugs undergo oxidation-reduction of the hydroxy/keto group at C17 [ 7 ] . This makes the compound more H2O soluble and therefore easier to be excreted.

Some metabolising enzymes behave otherwise and undergo different types of reactions when in different cells. An illustration is carbonyl reductases within tumour cells and normal cells. These have become a mark of new drugs such as oracin in the intervention of chest malignant neoplastic disease [ 9 ] . The enzymes within the malignant neoplastic disease cells metabolise oracin and doxorubin more efficaciously than in normal cells therefore cut downing the efficaciousness of the cytostatic consequence of the drugs.

Some carbonyl compounds nevertheless do non undergo decrease via the cytochrome P450 tract but are instead reduced by other tracts including the aldo-keto reductases ( AKR ) . An illustration is a drug incorporating a 1,3-diketone derivative S-1360 which upon decrease produces a cardinal metabolite HP1 which constitutes a major clearance tract [ 9 ] .

Nitrogen compounds:

The decrease of N incorporating compounds are reduced to aminoalkanes in order to help elimination as aminoalkanes are more H2O soluble than their nitro groups. Azo compounds on the other manus may be metabolised within the organic structure to bring forth the active drug as opposed to the precursor which may be formulated to acquire go through the first base on balls consequence or the hydrophilic barrier in order to come in their mark cells. The azo group provides 2 compounds with aminoalkane groups which can be farther metabolised like any other aminoalkane. Both of these functional groups are both reduced by cytochrome P450 enzymes and are NADPH dependant.


This is portion of the Phase I metabolism pathway. The metabolites produced are all susceptible to Phase II junction and therefore being excreted after the junction. The functional groups of the drugs that are metabolised by hydrolysis include esters and amides, which produce carboxylic acids, intoxicants and aminoalkanes. Esters are hydrolysed quicker than amides in vivo. Unlike oxidization and decrease the reactions are typically non carried out by the cytochrome P450 system. The most important 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 add-on which enantiomorph of the drug is generated. Some of these merchandises are toxic and unsafe to the organic structure.

Amino acid reactions

Several stage I reactions produce a carboxylic acid metabolite. Xenobiotic carboxylic acids can be metabolised before riddance by amino acerb junction. Glycine ; the most common conjugating amino acid signifiers ionic conjugates that are H2O soluble with aromatic, arylaliphatic and heterocyclic carboxylic acids. In these reactions, foremost the xenobiotic carboxylic acid is activated by ATP to organize the AMP 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 hence H2O soluble, hence it is easy eliminated in the piss and gall. ( 1 )

Glutathione junction

Glutathione is a protective compound in the organic structure that removes potentially toxic electrophilic compounds and xenobiotics. Drugs are metabolised by stage I reactions to organize strong elecrophiles that can respond with glutathione to organize conjugates that are non toxic. This stage II reaction differs from others since electrophiles are capable to junctions instead than nucleophiles. The nucleophilic thiol group on the glutathione compound ( figure 2 ) onslaughts elecrophiles ( electrophilic Cs with go forthing groups ) .

Compounds that can be conjugated to give thioether conjugates of glutathione:

  • Epoxides
  • Alkyl halides
  • Nitroalkanes
  • Alkenes
  • Aromatic halo- and nitro- compounds

Glutathione-S-transferases ( GST ) are enzymes which catalyse the reactions above. There are 13 different human GST fractional monetary units which have been identified and they belong to five different categories. They are located in the cytosol of the liver, kidney and intestine. The enzyme GST is thought to increase the ionization of the thiol group of glutathione, taking to an addition in its nucleophilicity towards electrophiles. ( 1 ) ( 2 )

Once formed, GSH conjugates may be excreted straight or more frequently they are farther metabolised to N-acetylcysteine conjugates which can so be excreted via ‘phase III metamorphosis ‘ .

Phase III Metabolism – farther alteration and elimination

Before being excreted in the piss, most xenobiotics are made less toxic and more H2O soluble as mutual opposition additions by metabolizing enzymes in stage II reactions. In stage III metamorphosis H2O soluble compounds are excreted in the piss. However, some drug compounds are non metabolised and hence are non excreted. These non-metabolised compounds are readily reabsorbed from the piss through the nephritic cannular membranes and into the plasma to be recirculated. ( 3 )

Some xenobiotic conjugates from stage II reactions are farther metabolised during stage III metamorphosis reactions. Glutathione-S conjugates may be metabolised farther 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 ensuing in a cysteine conjugate incorporating a free amino group of the cysteine residue. This so undergoes N-acetylation to organize mercapturic acid. The concluding merchandises ; mercapturic acids are S-derivatives of N-acetylcysteine synthesised from glutathione ( figure 4 ) . ( 1 ) ( 2 )

First-pass Metamorphosis

The metamorphosis of many drugs is dependent on the path of administation hence orally administered drugs are capable to first base on balls metamorphosis and accordingly their bioavailablity is reduced. This occurs as a consequence of the orally administered drugs come ining the systemic circulation via the hepatic portal vena, so the drug is exposed to the enteric wall and the liver, which is thought to be the chief site of first-pass metamorphosis of orally administered drugs. Other possible sites are the GI piece of land, blood, vascular endothelium and lungs.

First-pass Metabolism in the Liver

During first-pass metamorphosis, the cytochrome P450 enzymes household represent the most important 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 single isozymes within subfamilies, merely five P450 enzymes are shown to be important for the procedure of first-pass metamorphosis:

  • CYP1A2
  • CYP2C9
  • CYP2C19
  • CYP2D6
  • CYP3A4

Cytochrome P450 drug substrates are normally extremely extracted during first-pass metamorphosis. Examples of these drugs are ; morphia, Calan, propranolol, Versed, Lidocaine. Drugs that are extremely extracted such as Lidocaine have a low bioavailability when taken orally therefore they are non administered orally. CYP3A4 is the most normally active isozyme against P450 drug substrates. This is perchance due to the enzyme ‘s copiousness and wide substrate specificity. Highly extracted substrates for conjugative, reductive or non-P450 oxidative enzymes are less common. These include Trandate, morphia, terbutaline, Isuprel and Trental.

The intestine is besides an of import organ involved in pre-systemic metamorphosis. Metamorphosis here for drugs with high first-pass metamorphosis leads to a reduced bioavailability. Some metabolising enzymes such as CYP3A4 is found at a higher degree in enterocytes than in the liver. Recent findings province that intestine wall metamorphosis is the major cause of low bioavailability of certain drugs.

Intestinal First-pass Metamorphosis

Assorted drug metabolising enzymes found in the liver are besides found within the epithelial tissue of the GI piece of land. These include cytochromes P450, glucuronosyl transferases, sulfotransferases, N-acetyl transferase, glutathione S-transferases, esterases, epoxide hydrolase and intoxicant dehydrogenase. The little bowel contains high sums of three cytochrome P450 enzymes ; CYP3A, CYP2D6 and CYP2C. Unlike the liver which has a comparatively unvarying distribution of P450enzymes, the distribution of P450 enzymes is non unvarying along the little bowel and villi. Proximal mucosal P450 content is usually higher than distal mucous membrane P450 content.

Therefore it has been established that protein degree and catalytic activity of drug-metabolizing enzymes in the little bowel are by and large lower than those in the liver. This has been demonstrated by comparing of cytochrome P450 enzymes in the liver and the little bowel. The extent of first-pass metamorphosis can ensue from interindividual variableness:

  1. Familial fluctuation
  2. Initiation or suppression of metabolic enzymes
  3. Food additions liver blood flow. This can increase the bioavailablity of some drugs by increasing the sum of drug presented to the liver to an sum that is above the threshold for complete hepatic extraction
  4. Drugs that increase liver blood flow ( similar effects to nutrient ) and drugs that cut down liver blood flow
  5. Non- linear first base on balls dynamicss, i.e. dose
  6. Liver disease increases the bioavailability of some drugs with extended first-pass metamorphosis ( 4 )

To avoid first base on balls metamorphosis a drug can be administered sublingual and buccal paths. These paths lead to drugs being absorbed by the unwritten mucous membrane. During sublingual disposal the drug is put under the lingua where it dissolves in salivary secernments. An illustration of a sublingual drug is nitroglycerine. During buccal disposal the drug is positioned between the dentitions and the mucose membrane of the cheek. Both of these paths avoid devastation by the GI fluids and first base on balls consequence of the liver. Drugs may besides be administered via other paths to avoid first-pass metamorphosis, for illustration ; rectal, inspiration, transdermic, endovenous. ( 5 )


Many drugs require metabolic activation in order to exercise their pharmacological action ; these are described as pro-drugs. There are two types ; type I and type II which has subtypes A and B dependant on the site of activation. Type I prodrugs are converted intracellularly at the mark cells ( A ) or at tissues that normally metabolise compounds ( B ) . An illustration of a type IA prodrug is Zidovudine and type IB prodrug is captopril. Metabolic activation of type I prodrugs is normally linked to phase I metabolic enzymes. Type II prodrugs are converted extracellularly in GI fluids ( A ) or in the systemic circulation ( B ) . An illustration of a type IIA prodrug is sulfasalazine and type IIB prodrug is fosphenytoin. Type II prodrugs are really popular as they are involved in get the better ofing bioavailability jobs, which are normally experienced with many drugs, by bettering permeableness and cut downing the first base on balls consequence. ( 6 )

Type I Prodrugs are used to aim a drug to its specific site of action ; an illustration of this is the drug used in Parkinson ‘s disease L-dopa ; the inactive signifier of the drug which is metabolised in the neurone by the enzyme dihydroxyphenylalanine decarboxylase to the active signifier ; Dopastat. Dopamine does non traverse the blood-brain barrier so it is given as the L-dopa precursor which is lipotropic so it can traverse the barrier and so metabolized in vivo to dopamine. ( 7 )

Another illustration of the usage of prodrugs is the pharmacological activation of a type II prodrug Azathioprine to mercaptopurine which is a chemotherapeutic agent used in the intervention of leukemia. When Purinethol is administered, its clinical utility 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 administrating Purinethol as its cysteine conjugate, the restrictions can be overcome. This ionic signifier of the pro-drug conjugate is selectively taken up by the nephritic organic anion conveyance system. The kidney B-lyase enzyme system so cleaves the prodrug conjugate to give the active Purinethol in the kidney ( figure 5 ) . ( 8 ) ( 9 )

To reason, prodrugs can be metabolised in different ways to organize the active drug. They can be used to aim specific sites, better soaking up and better unwritten bringing of ailing water-soluble drugs. They can besides be used to avoid first base on balls metamorphosis in drugs with high first base on balls extraction and cut down toxicity. ( 6 )

Factors impacting metamorphosis

There are several factors that can impact drug metamorphosis. Age, sex, inducers and inhibitors are some of which can consequence drug metamorphosis which are mentioned below.

How does age affect drug metamorphosis:

There are many physiological alterations that occur with ripening. The alterations have the possible to impact both drug temperament and metamorphosis. Drug metamorphosis is chiefly functioned by the liver, its size, blood perfusion and man-made capacity for proteins which all determine the rate of hepatic drug riddance [ 5 ] .

Pediatric population

Phase one and phase two metabolic tracts may non be active at birth due to maturational alterations. The pediatric population and aged population have differences in their capacity to metabolize a drug which can therefore bring forth a lower or higher plasma concentration of active substances compared with grownups depending on the enzyme system used. There are illustrations of metabolites produced by curative agents in kids that are non normally seen in grownups. The metabolites produced possibly the ground for some of the efficaciousness and or toxicity seeable with drug disposal in kids. An illustration is: caffeine production in a neonate receiving Theophylline. Other curative agents which show alterations in metabolite production in kids are ;

  • Valproic acid,
  • paracetamol,
  • Chloramphenicol,
  • Cimetidine
  • Salicylamide.

In most instances the differences that occur between kids and grownups are in the ratios of the metabolites relative to the parent drug instead than in new metabolites single to the pediatric population with some exclusions. The pediatric population shows the same set of enzymes as the grownup population. ( 1 )

In general age related alterations in drug metamorphosis have been shown to happen due to a effect of lessened enzyme activities within the aged human liver due to the size of the liver decreasing and hepatic blood flow diminishing. With age the liver blood flow is by and large reduced by about 20-30 % and there is a lessening in liver size by about ( 17-36 % ) .

Presently there is no clear form ; nevertheless there are two general tendencies that influence the rate of metamorphosis. One tendency is that drugs that are undergoing hepatic microsomal oxidization are more likely to be metabolised easy in the aged and those which are conjugated are non likely to be influence by the age factor. Second, drugs that have high hepatic clearance, extraction ratios example-Chlormethiazole, and Labetalol and undergo extended first base on balls metamorphosis whilst unwritten soaking up may demo a big addition in bioavailability in the aged.

Aged population

In general in the aged population hepatic blood flow decreases up to 40 % and there can be a considerable decrease in the sum of drug making the liver per unit. Surveies have shown that the consequence of ageing on liver enzymes with peculiar drug that are capable to oxidative stage 1 metamorphosis have decreased riddance. This is due to the fact that stage 1 metamorphosis is catalyzed by the P450 system in the smooth endoplasmic Reticulum of hepatocytes.This procedure slows down a batch with age. Phase two metamorphosis is non known to be age associated.


Decrease microsomal hepatic oxidization
Decrease in clearance
Addition in steady -state degrees
Increase in half lives
Increase degrees of active metabolites
Decrease first base on balls metamorphosis

As said mentioned before the hemoperfusion of the liver declines in aged and drugs that have a high extraction show an age related lessening in metabolic clearance as blood which moves via the liver is largely cleared from these compounds. This is known as blood flow limited metamorphosis ( shown in table 2 ) In most instances drugs that have low hepatic extraction do non hold a reduced metabolic clearance. This is because it is non dependent on hepatic blood flow but alternatively on the entire tissue content of metabolizing enzymes. This is called capacity limited metamorphosis ( shown in table 2 ) ( 6 )

How make Sex differences affect drug metamorphosis?

Another factor that affects drug metamorphosis is sex differences. Sexual activity differences in pharmokinetics and pharmacodynamics characterize many drugs and have effects on single differences in drug efficaciousness and toxicity.Sex based differences in drug metamorphosis are the chief cause of sex dependant pharmokinetics.They besides reflect underlying alterations in the look of hepatic enzymes active in the metamorphosis of:

  • Drugs
  • Steroids
  • Fatty acids
  • Environmental chemicals including ; cytochrome p450, sulfotransferases, glutathione transferases and UDP-glucuronosyltransferases.

The CYP450 group of enzymes is the chief drug metabolizing system used in humans.CYP450 enzymes have shown to hold important sex differences. It has been demonstrated that some major CYP450 enzymes have important differences depending on gender. As mentioned earlier there are different stages of drug metamorphosis. Different stages have different enzymes which may hold differences in their action depending on their action.

Phase 1 metamorphosis and gender differences:

CYP1A2 and CYP1A2 enzymes are involved in stage 1 metamorphosis. They are involved in the clearance of certain medicine which includes ; Caffeine and Theophylline.There has been experimental informations grounds to demo that ;

  • Theophylline metamorphosis was faster in work forces than adult females.
  • Urinary concentrations of caffeine metabolites revealed lower CYP1A2 activity in adult females.
  • Antipsychotic agents ; Thiothixene, Olanzapine and Clozapine which are all CYP1A2 substrates have a higher clearance in work forces than adult females

Females have a prevailing look of CYP3A4 which is one of the most of import accelerators of drug metamorphosis in the liver. There is a batch of grounds that supports that the differences in sex have an impact on these enzymes. Many drug substrates for CYP3A4 have a higher clearance in adult females. Drugs that have been found to hold a higher clearance in adult females include ; Cyclosporine, Erythromycin, Tirilazad, Verapamil, Nifedipine, Diazepam and Alfentanil.

CYP2D6 is the 2nd most frequent enzyme used in the metamorphosis of curative drugs. Many medicines are partly or to the full metabolised by CYP2D6 ;

Examples of drugs metabolised by CYP2D6 and sex differences in their action ;

  • Sertraline is a CYP2D26 substrate which is found to be higher in immature work forces compared to females.
  • Oral clearance of Desipramine has been found greater in males compared to females.
  • Mirtazapine is an antidepressant which is metabolised mostly by CYP2D6 and CYP3A and has shown to hold a faster clearance in work forces.

Sexual activity differences in stage Two metamorphosis:

There is some grounds that suggests that there are sex differences in the metamorphosis of glucuronidation of some curative compounds.

Inducers impacting drug metamorphosis:

This is the procedure where enzyme activity is enhanced due to increased enzyme synthesis. An e.g. of this is Rifampicin selectivity induces CYP384.The group of P450 isoform shows great selectivity of initiation. Enzyme initiation has a practical effect, in that when two or more drugs are given at the same time, the inducer speeds up the drug metamorphosis of other drugs ( 4 ) . Examples of drugs which cause enzyme initiation are: Rifampicin, Carbamazepine, Ethanol and Phenobarbitone. ( 2 )


There are many drugs that exert their curative consequence by enzyme suppression Example: Methrotrexate, Angiotensin change overing enzyme inhibitors, non-steroidal anti-inflammatory drugs ) .inhibition of drug metamorphosis by a at the same time administered drug finally can do drug accretion and toxicty.Certain inhibitors have selectivity for p450 isoforms, an illustration is- Ketoconazole in comparing to example- Cimetidine which inhibit all cytochrome p450-mediated metamorphosis. ( 4 ) Both the drugs both of the drugs Coumadin and Phenytoin compete with each other in their metamorphosis when given together. This consequences in the addition of drug concentration in plasma of both drugs. Examples of drugs which inhibit cytochrome p450: Cimetidine, Erythromycin, Ciprofloxacin, Isoniazid and Chloramphenicol.


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