The genetic control of drug oxidation in the liver

Abstract

Hepatic drug oxidation is a major source of interindividual variations in drug behaviour. A wide spread of the pharmacokinetic parameters of extensively oxidized drugs is a common observation. For such compounds, in the absence of polymodal distribution of the kinetic parameters, no distinct genetic influence can be detected. The discovery that the urinary excretion of debrisoquine and its main hydroxylated metabolite displays a bimodal pattern opened a new field in the study of hepatic metabolism. This new genetic polymorphism now concerns the oxidative metabolism of numerous substances such as antihypertensive agents, antidepressants, antiarrhythmic drugs and various other unrelated compounds. The poor metabolizer phenotype is observed in some 8% of individuals in European populations. We have shown that the oxidative metabolism of beta-adrenoceptor blocking drugs is under the same genetic control as debrisoquine. Using bufuralol as a test drug, we have studied the influence of polymorphic oxidation on interindividual variations of parent drug and metabolite plasma concentrations. It appears clearly that oxidation polymorphism is a major factor of variability in hepatic drug handling. This fact has important clinical and pharmaceutical implications.