Variability in drug metabolism: importance of genetic constitution

In man wide variability exists in the rate of metabolism of drugs and among factors which contribute to this phenomenon genetic constitution is of major importance. The metabolism of a number of drugs is subject to polymorphism and the frequency distribution of particular pharmacokinetic parameters shows bimodality, with poor (PM) and extensive metabolizers (EM). Acetylation of a number of drugs is known to be polymorphic and the incidence of poor metabolizers varies markedly among different populations. Debrisoquine and sparteine are frequently applied model substrates for the characterization of a polymorphism in oxidative metabolism. Polymorphic drug oxidation may have important clinical implications, because when standard dosage regimens are applied plasma concentrations will reach far above the maximum acceptable in poor metabolizers and consequently side effects may arise. Regarding the multiplicity of the drug oxidizing enzyme system (cytochrome P-450) it could be of interest to combine model substrates in a cocktail to be able to characterize human subjects simultaneously for a number of independent polymorphisms.