Microsomal Enzyme Induction & Enzyme Inducers (Pharmacokinetics Part 10) by Dr. Shikha Parmar


Drug metabolism is the term used to describe the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily. The majority of metabolic processes that involve drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated there.

The purpose of metabolism in the body is usually to change the chemical structure of the substance, to increase the ease with which it can be excreted from the body.

Drugs are metabolized through various reactions including:
(1) Oxidation
(2) Reduction
(3) Hydrolysis
(4) Hydration
(5) Conjugation
(6) Condensation
(7) Isomerization

There are often two phases of drug metabolism.
(1) Phase I: Non-synthetic reactions such as cleavage (e.g. oxidation, reduction, hydrolysis), formation or modification of a function group.
Phase I reactions convert a parent drug to more polar (water-soluble) active metabolites by unmasking or inserting a polar functional group (-OH, -SH, -NH2) geriatric patients have decreased phase I metabolism. Drugs metabolized via phase I reactions have longer half-lives.
(2) Phase II: Synthetic reactions such as conjugation with an endogenous substance (e.g. sulfate, glycine, glucuronic acid).

Enzyme induction refers to an increase in the rate of hepatic metabolism, mediated by increased transcription of mRNA encoding the genes for drug-metabolizing enzymes. This leads to a decrease in the concentrations of drugs metabolized by the same enzyme. Rifampicin is a potent inducer of CYP3A4 and can result in clinically significant decreases in plasma concentrations of many concomitant medications including PIs, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and entry inhibitors. It is important to keep in mind that the doses of many concomitant medications will need to be adjusted when starting or stopping enzyme inducers. Similar to the clinical recommendations for enzyme inhibitors, the dosing guidelines for enzyme inducers fall into three broad categories:

Contraindicated—e.g. rifampicin plus etravirine as co-administration may cause significant decreases in etravirine concentrations and lack of clinical efficacy.

Dose adjustment recommended—e.g. Current guidelines recommend increasing the dose of efavirenz from 600 to 800 mg daily when co-administered with rifampicin to overcome the inducing effects of rifampicin.

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