Clinical significance of the sparteine/debrisoquine oxidation polymorphism

Abstract

The sparteine/debrisoquine oxidation polymorphism results from differences in the activity of one isozyme of cytochrome P450, the P450db1 (P450 IID1). The oxidation of more than 20 clinically useful drugs has now been shown to be under similar genetic control to that of sparteine/debrisoquine. The clinical significance of this polymorphism may be defined by the value of phenotyping patients before treatment. The clinical significance of such polymorphic elimination of a particular drug can be analyzed in three steps: first, does the kinetics of active principle of a drug depend significantly on P450db1?; second, is the resulting pharmacokinetic variability of any clinical importance?; and third, can the variation in response be assessed by direct clinical or paraclinical measurements? It is concluded from such an analysis that, in general, the sparteine/debrisoquine oxidation polymorphism is of significance in patient management only for those drugs for which plasma concentration measurements are considered useful and for which the elimination of the drug and/or its active metabolite is mainly determined by P450db1. At present, this applies to tricyclic antidepressants and to certain neuroleptics (e.g. perphenazine and thioridazine) and antiarrhythmics (e.g. propafenone and flecainide). Phenotyping should be introduced in to clinical routine under strictly controlled conditions to afford a better understanding of its potentials and limitations. The increasing knowledge of specific substrates and inhibitors of P450db1 allows precise predictions of drug-drug interactions. At present, the strong inhibitory effect of neuroleptics on the metabolism of tricyclic antidepressants represents the best clinically documented and most relevant example of such an interaction.