ROLE OF POLYMORPHIC DEBRISOQUIN 4-HYDROXYLASE ACTIVITY IN THE STEREOSELECTIVE DISPOSITION OF MEXILETINE IN HUMANS

It was reported previously that mexiletine undergoes stereoselective d isposition in humans and that formation of three of its major metaboli tes co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-med iated oxidation pathways of mexiletine are responsible for the stereos elective disposition of the racemate in humans. Fourteen healthy subje cts (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) pa rticipated in this study. They received a single 200-mg oral dose of r acemic 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 administrat ion of mexiletine and analyzed by a stereoselective high-performance l iquid chromatography assay. As reported previously, RS-mexiletine disp osition 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 P Ms. 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 rati o 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-depen dent metabolic pathways are responsible for the stereoselective dispos ition of mexiletine in humans.