Role of polymorphic debrisoquin 4-hydroxylase activity in the stereoselective disposition of mexiletine in humans.

It was reported previously that mexiletine undergoes stereoselective disposition in humans and that formation of three of its major metabolites co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-mediated oxidation pathways of mexiletine are responsible for the stereoselective disposition of the racemate in humans. Fourteen healthy subjects (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) participated in this study. They received a single 200-mg oral dose of racemic mexiletine hydrochloride on two occasions: once alone and once during administration of low-dose quinidine (50 mg four times a day). Blood and urine samples were obtained over 48 hr after the administration of mexiletine and analyzed by a stereoselective high-performance liquid chromatography assay. As reported previously, RS-mexiletine disposition was altered by a genetically determined (PM) or drug-induced (quinidine) decrease in CYP2D6 activity. In contrast, R/S ratio of the apparent total and nonrenal clearances of mexiletine and the R/S ratio of the urinary recovery of both enantiomers were similar in EMs and PMs. Moreover, these ratios were unaltered by quinidine administration. Partial metabolic clearance of N-hydroxymexiletine glucuronide, a non-CYP2D6 dependent metabolite, was highly stereoselective; the R/S ratio was 11.3 +/- 3.4. This ratio was similar in subjects with either an EM or a PM phenotype and was not altered by quinidine administration. Thus, the results obtained in this study suggest that non-CYP2D6-dependent metabolic pathways are responsible for the stereoselective disposition of mexiletine in humans.

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.