Clinical implications of enzyme induction and enzyme inhibition

The pharmacological effect of a drug is partly dependent upon its concentration at its site of action, which in turn is partly dependent upon its rate of elimination. The rate of elimination of many lipophilic drugs is governed by the activity of the hepatic microsomal mixed-function oxidases. Consequently any alteration in the activity of these enzymes may result in a modification of drug action. A wide range of chemically unrelated substances may stimulate the activity of the mixed-function oxidases by enzyme induction. The drugs most frequently encountered as enzyme-inducing agents in man are barbiturates, rifampicin and phenytoin. Enhancement of drug metabolism by ethanol, tobacco smoking and diet may also involve enzyme induction. Enzyme induction is normally associated with a reduction in the drug efficacy but may also alter the toxicity of certain substances. Enzyme induction has been assessed in man by measuring changes in the pharmacokinetics of a marker drug, or changes in the disposition of endogenous compounds such as gamma-glutamyltranspeptidase, D-glucaric acid and 6beta-hydroxycortisol. The therapeutic problems associated with enzyme inhibition have received much less attention than those associated with enzyme induction. The effect on the rate of elimination of a particular drug will depend upon the fraction of the dose that is normally metabolised by the inhibited enzyme and on the affinity of the enzyme for the drug and the inhibitor. An alteration in the dosage schedule is usually only necessary for drugs with a small therapeutic ratio.