Drug metabolism

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DRUG METABOLISMPresented By:-Dr. Roohana HasanJR-1

IntroductionDrug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.Biotransformation means chemical alteration of the drug in the body. The metabolites formed are less lipid soluble.

What does biotransformation do?It converts lipid soluble compounds to lipid insoluble so that they are not reabsorbed.Role of biotransformation:defensive mechanismincreases polarity of drug molecules, restricts penetration through cellular membranereduces distributionpromotes elimination

Sites of MetabolismLiver GITLungsKidneyPlasmaSkinNasal Mucosa Others

Consequences of BiotransformationInactive metabolite from an active drug

Active metabolite from an active drug

Active metabolite from an inactive drug

Chemical PathwaysPhase 1 reactionsMainly microsomal - oxidation reduction hydrolysis

2. Few non microsomal-

3. Metabolite may be active or inactive.

Phase 2 reactions

Synthetic/Conjugation reactions

Can be catalysed by microsomal, mitochondrial or cytoplasmic enzymes.

Metabolite mostly inactive

Endogenous radical

Structure of Cytochrome

Location of CYPs in the Cell

CYP- Oxidoreductase Complex

RH+02+NADPH+H+ ---------------- R0H+H20+NADP+

Drug Metabolising Enzymes


Reactions involved in Drug MetabolismOxidation- This reaction involves addition of oxygen /negatively charged radical or removal of hydrogen /positively charged radical. Oxidations are the most important drug metabolizing reactions. Various oxidation reactions are: hydroxylation;oxygenation at C,N or S atoms; N or 0-dealkylation, oxidative deamination, etc.

Oxidative reactions are mostly carried out by a group of monooxygenases in the liver which in the final step involve a cytochrome P-450 haemoprotein, NADPH, cytochrome P-450 reductase and molecular 02. More than 100 cytochrome P- 450 isoenzymes differing in their affinity for various substrates (drugs) have been identified.Eg Imipramine, diazepam, codiene, phenytoin, barbiturates, paracetamol.

Reduction- A chemical reaction in which hydrogen s added to, or oxygen is removed from a compound.

Alcohols, aldehydes, quinones are reduced.

Drugs -chloralhydrate, chloramphenicol, halothane, warfarin.

Hydrolysis -This is cleavage of drug molecule by taking up a molecule of water.

Ester + H20 Esterase Acid + Alcohol

Hydrolysis occurs in liver, intestines, plasma and other tissues.

Examples are choline esters, procaine, lidocaine, procainamide, aspirin, c

Flavin containing Monooxygenases (Zieglers enzyme)Super family of phase I enzymes expressed at high levels in the liver bound to ER.Six families of FMOs, FMO3 most abundant in the liver.Metabolize nicotine, H2 receptor blocker, antipsychotics [clozapine], antiemetics [itopride].Genetic deficiency Fish odor syndrome due to lack of metabolism of TMAO [ trimethylamine N oxide ] TMA.Minor contributors to drug metabolism - produce benign metobolites.Not involved in drug-drug interactions.Eg : Itopride metabolized by FMO3 : Cisapride metabolized by CYP3A419

Conjugation EnzymesPhase 2 conjugation enzymes are synthetic in nature result in formation of metabolite with increase in molecular mass.Terminate biological activity of the drug.Characteristic feature dependency on the catalytic reaction for cofactors such as UDP-GA, & PAPS,for UGT & SULT, which react with available functional groups on the substrates.All reactions are carried out in cytosol of the cell, exception of glucuronidation.Catalytic rates of phase 2 reaction are significantly faster than rates of CYPs. So rate of elimination depends on Phase 1.20

GlucuronidationMost important phase 2 reaction catalyzed by UDP-Glucuronosyltransferases (UGTs).UGT2 Greater specificity for glucuronidation of steroids.UGT1A1 Glucuronidation of bilirubin. Crigler Najjars syndrome type 1 & type 2 Most common genetic polymorphism Gilberts syndrome (10% popuplation) (mutation in UGT1A1 gene).


SulfationSULT located in cytosol, metabolise various substrates.13 SULT isoforms identified role in human homeostasis.SULT1B1 catalysis of cholesterol .SULT1A3 selective for catecholamineSULT1E1 estrogens are sulfatedSULT2A1 DHEASULT1 Sulfation of phenolic molecules. Eg:- acetaminophen and minoxidil.SULT1A1 Most abundant in human tissue.


Glutathione conjugationThe glutathione-S-transferases (GSTs) catalyze the transfer of glutathione to reactive electrophiles, a function that serves to protect cellular macromolecules from interacting with electrophiles that contain electrophilic heteroatoms (-O, -N, and -S) and in turn protects the cellular environment from damage.

Glutathione exists in the cell as oxidized (GSSG) or reduced (GSH) forms, and the ratio of GSH:GSSG is critical in maintaining a cellular environment in the reduced state.

A severe reduction in GSH content can predispose cells to oxidative damage.

Over 20 human GSTs have been identified and divided into two subfamilies: the cytosolic and the microsomal forms. The major differences in function between the microsomal and cytosolic GSTs reside in the selection of substrates for conjugation; The cytosolic forms have more importance in the metabolism of drugs and xenobiotics, Whereas the microsomal GSTs are important in the endogenous metabolism of leukotrienes and prostaglandins.

N-acetylationThe cytosolic N-acetyltransferases (NATs) are responsible for the metabolism of drugs and environmental agents that contain an aromatic amine or hydrazine group.

NATs are among the most polymorphic of all the human xenobiotic drug-metabolizing enzymes.

There are two functional NAT genes in humans, NAT1 and NAT2.

The therapeutic relevance of NAT polymorphisms is in avoiding drug-induced toxicities. 26

NAT1 is ubiquitously expressed among most human tissues, whereas NAT2 is found predominantly in liver and the GI tract.

MethylationXenobiotics undergo O-, N-,S- methylation.N-methyltransferase are COMT, POMT, TPMT.The common theme among the MTs is the generation of a methylated product, substrate specificity is high and distinguishes the individual enzymes.TPMT catalysis the S- methylation of aromatic and cyclic sulfhydryl compounds.Genetic deficiency of TPMT severe toxicities of thio purine drugs.(Azathioprine , 6-mercaptopurine )28


Enzyme InductionDrugs on repeated administration stimulate the growth of smooth endoplasmic reticulum.

This induction usually reversible, leads to increased microsomal enzyme activity.

Therefore, metabolism is increased and pharmacological response in decreased.

Mostly in liver, but can also occur in intestine, lung, placenta, kidney.

It reduces efficacy and potency of drugs metabolized by these enzymes.It reduces plasma half-life and duration of action of drugs.It enhances drug tolerance.It increases drug toxicity by enhancing concentration of metabolite, if metabolite is toxic.It increases chances of drug interactions.Can be used for therapeutic benefits.

Clinical importance of enzyme induction


Induction of Metabolism

31CYP 450 enzymes and their inducers

CYP3A4 Induction By Atorvastatin

It takes 3-10 days to induce and 1-3 weeks to return to normal levels after stoppage of inducer32Atorvastatin

Enzyme InhibitionOne drug may inhibit the metabolism of another drug with resultant increase in the circulating levels of the slowly metabolised drug and prolongation of its pharmacological effects.

Enzyme inhibition can be of hepatic microsomal MFOs or of enzymes having specific functions. Eg:xanthine oxidase, monoamine oxidase.

Rapid and usually reversible process.


CimetidineHepatic microsomal mixed function oxidasePhenytoin, Warfarin, Anti Depressants, Theophyline, Diazepam, Quinidine, TestosteroneSodium valpaorateHepatic microsomal mixed function oxidasePhenytoin, phenobarbital, primidonErythromycinHepatic microsomal mixed function oxidaseTheophyline, Warfarin, carbamazepine, cyclosporinDisulfiran,tolbutamide,metranidazoleAldehyde dehydrogenaseAlcohol,WarfarinCarbidopaL-aromatic aminoacid decorboxylaseL-dopa


Clinical significanceAdverse consequencesUnexpected nausea, vomiting and tremors may occur when Theophylline is given with erythromycin.

Enhanced bleeding tendency when Dicumerol is given with cimetidine.

Severe respiratory depression may occur when Morphine is given with MAOs.

Therapeutically beneficial consequencesIncreased accessibility of L-dopa in brain when given along with carbidopa.

Aversion to alcohol after prior administration of disulfiram.

Reversal of skeletal muscle paralysis due to tubocurarine by neostigmine.

Factors affecting Drug MetabolismAge




Genetic variations

Nutrition and diet

Role of Xenobiotic Metabolism in the Safe and Effective Use of DrugsMetabolism normally results in the inactivation of their therapeutic effectiveness and facilitates their elimination.

The extent of metabolism can determine the efficacy and toxicity of a drug by controlling its biological t1/2.

If a drug is metabolized too quickly, it rapidly loses its therapeutic effi