[The significance of cytochrome P450 gene superfamily for the clinical pharmacokinetics of drugs]

Abstract

It is presumed that there are between 20 and 200 medicamentoxidizing cytochrome P450 isozymes. The formation of every P450 isozyme is encoded by a separate gene and the P450 gene superfamily is classified into families and sub-families on the basis of the degree of amino acid relationship for the isozymes which are coded. The genetic polymorphism for 4-hydroxylation of the anti-epileptic preparation S-mephenytoin is associated with an isozyme in the P450IIC sub-family. In Denmark, approximately 3% of the population are poor metabolizers (PM) of mephenytoin. Mephenytoin polymorphism appears to be partially responsible for N-demethylation of diazepam and imipramine but the clinical significance of this is still obscure. Recent investigations suggest that conversion of proguanil to the active metabolite, cycloguanil, is reduced in mephenytoin-PM. The sparteine/debrisoquine-oxidation polymorphism is associated with P450IID6 isozyme and 7-8% of the Danish population are PM. The sparteine/debrisoquine polymorphism is of significance for elimination of more than 20 different medicaments with clinically significant consequences for tricyclic antidepressants, certain neuroleptic and certain antiarrhythmic drugs. P450IIIA4 is the third isozyme with demonstrated significance for elimination of clinically significant medicaments including cyclosporin A. No genetic polymorphism has, as yet, been demonstrated for this isozyme.