Metabolism Of Drugs

Drugs are chemical substances, which interact with living organisms and produce some pharmacological effects and then, they should be eliminated from the body unchanged or by changing to some easily excretable molecules. The process by which the body brings about changes in drug molecule is referred as drug metabolism or biotransformation.

Enzymes responsible for metabolism of drugs:

a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450.
b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g. esterases, amidase, hydrolase.
Types of biotransformation: The chemical reactions involved in biotransformation are classified as phase-I and phase – II (conjugation) reactions. In phase-I reaction the drug is converted to more polar metabolite. If this metabolite is sufficiently polar, then it will be excreted in urine. Some metabolites may not be excreted and further metabolised by phase –II reactions.
Phase-I: Oxidation, reduction and hydrolysis.
Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation reactions.
Phase – I reactions
a) Oxidation: Microsomal oxidation involves the introduction of an oxygen and/or the removal of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule e.g. conversion of salicylic acid into gentisic acid.
b) Reduction: The reduction reaction will take place by the enzyme reductase which catalyze the reduction of azo (-N=N-) and nitro (-NO2) compounds e.g. prontosil converted to sulfonamide.
c) Hydrolysis: Drug metabolism by hydrolysis is restricted to esters and amines (by esterases and amidases) are found in plasma and other tissues like liver. It means splitting of drug molecule after adding water e.g. pethidine undergoes hydrolysis to form pethidinic acid.
Other drugs which undergo hydrolysis are atropine and acetylcholine.
Phase – II reactions (conjugation reactions):
This is synthetic process by which a drug or its metabolite is combined with an endogenous substance resulting in various conjugates such as glucoronide, ethereal sulfate, methylated compound and amino acid conjugates.
Glucuronide conjugation: It is the most common and most important conjugation reaction of drugs. Drugs which contain
a) Hydroxyl, amino or carboxyl group undergo this process e.g. phenobarbitone.
b) Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa and kidney, which transfers sulfate group to the drug molecules e.g. phenols, catechols, etc.
c) Acetyl conjugation: The enzyme acetyl transferase, which is responsible for acetylation, is present in the kupffer cells of liver. Acetic acid is conjugated to drugs via its activation by CoA to form acetyl CoA. This acetyl group is then transferred to-NH2 group of drug e.g. dapsone, isoniazid.
d) Glycine conjugation: Glycine conjugation is characteristic for certain aromatic acids e.g. salicylic acid, isonicotinic acid, p-amino salicylic acid. These drugs are also metabolized by other path ways.
e) Methylation: Adrenaline is methylated to metanephrine by catechol-o-methyl transferase.
Here the source of methyl group is s – adenosyl methionine.