Drug Metabolism

Lailaturrahmi 0811012047
Fakultas Farmasi Universitas Andalas

Definition
Drug metabolism is the chemical alteration of a drug by the body.

Effects of Drug Metabolism

The drug is made more hydrophilic Metabolite is usually less active than parent drug (not always occurred)

Location of Drug Metabolism

Liver Lung Kidney Small intestine Colon Skin Adrenal gland

A vast majority of drugs pass through the liver, which is the site of most drug metabolism. In the liver, enzymes convert : prodrugs active metabolites active drugs inactive forms.

FirstFirst-pass effect/metabolism
All orally administered drugs pass through the liver to the systemic circulation This term does not refer to hepatic metabolism only

Drug Biotransformation Reactions

Active drug to inactive metabolite Deamination (Amphetamine Phenylacetone) Hydroxilation (Phenobarbital Hydroxyphenobarbital)

Active drug to active metabolite Demethylation (Codeine Morphine) Acetylation (Procainamide Nacetylprocainamide) Hydroxilation (Phenylbutazone Oxyphenbutazone)

Inactive drug to active metabolite

Hydrolysis (Hetacillin Ampicillin) Azoreduction (Sulfasalazine Sulfapyridine + 5-aminosalycilic acid) 5-

Active drug to reactive metabolite

Aromatic hydroxylation

Pathway of Drug Biotransformation

Phase I (asynthetic reactions)
Oxidation Reduction Hydrolysis

Phase II (synthetic reactions)

Conjugation

Hepatic Enzyme Involved in Metabolism

Mixed function Oxidases Is responsible for reduction and oxidation of drugs and certain natural metabolites

Phase I reaction
There are 3 common reactions : oxidation, reduction, and hydrolysis Oxidation is the most common reaction The oxidation process involve NADPH, O2, NADPH-cytochrome PNADPHP450 reductase, and cytochrome PP450

Phase II reaction
Involve conjugation of drug/phase I metabolites with endogenous substances Type of conjugation : glucoronide, acetyl, glutathione, glycine, sulphate, methyl

Glucoronidation lucoronidation
Conjugating agent : glucoronic acid High energy metabolite : uridine diphosphoglucoronic acid (UDPGA) Functional group combined with : -OH, COOH, -NH2, -SH

Sulfation
Conjugating agent : sulfate High energy metabolite : 3'3'phosphoadenosine-5'phosphoadenosine-5'-phosphosulfate (PAPS) Functional group combined with : -OH, NH2,

Amino acid conjugation

Conjugating agent : glycine High energy metabolite : Coenzyme A thioesters Functional group combined with : -COOH

Acetylation
Conjugating agent : Acetyl CoA High energy metabolite : Acetyl CoA Functional group combined with : OH, NH2

Methylation
Conjugating agent : CH3 from SSadenosylmethionine High energy metabolite : SSadenosylmethionine Functional group combined with : OH, NH2

Glutathione (mercapturine acid conjugation)

Conjugating agent : Glutathione High energy metabolite : Arene oxides, epoxides Functional group combined with : Aryl halides, epoxides, arene oxides

Factor affecting drug metabolism

Enzyme induction Enzyme inhibition Genetic polymorphism Age

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