Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes

The cytochrome P-450dbl isozyme (P-450bdl) is responsible for the genetic sparteine-debrisoquine type polymorphism of drug oxidation in humans. To investigate the relationship between mexiletine oxidation and the activity of this isozyme, cross-inhibition studies were performed in human liver microsomes with mexiletine and dextromethorphan, a prototype substrate for P-450dbl. The formation of hydroxymethylmexiletine and p-hydroxymexiletine, two major mexiletine metabolites, was competitively inhibited by dextromethorphan. Mexiletine competitively inhibited the high affinity component of dextromethorphan O-demethylation. In addition, there was a good agreement between the apparent Km values for the formation of both mexiletine metabolites and the high affinity component of dextromethorphan O-demethylation and their respective apparent Ki values. Several drugs were tested for their ability to inhibit mexiletine oxidation. Quinidine, quinine, propafenone, oxprenolol, propranolol, ajmaline, desipramine, imipramine, chlorpromazine and amitryptiline were competitive inhibitors for the formation of hydroxymethylmexiletine and p-hydroxymexiletine as for prototype reactions of the sparteine-debrisoquine type polymorphism. Amobarbital, valproic acid, ethosuximide, caffeine, theophylline, disopyramide and phenytoin, known to be non-inhibitors of P-450dbl activity, were found not to inhibit the formation of these mexiletine metabolites. Moreover, the formation of both metabolites was strongly inhibited by an antiserum containing anti-liver/kidney microsomes antibodies type I (anti-LKMI) directed against P-450dbl. These data suggest that the formation of two major metabolites of mexiletine is predominantly catalysed by the genetically variable human liver P-450dbl.