PT  - JOURNAL ARTICLE
AU  - Abolfathi, Z
AU  - Fiset, C
AU  - Gilbert, M
AU  - Moerike, K
AU  - Bélanger, P M
AU  - Turgeon, J
TI  - Role of polymorphic debrisoquin 4-hydroxylase activity in the stereoselective disposition of mexiletine in humans.
DP  - 1993 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1196--1201
VI  - 266
IP  - 3
4099  - http://jpet.aspetjournals.org/content/266/3/1196.short
4100  - http://jpet.aspetjournals.org/content/266/3/1196.full
SO  - J Pharmacol Exp Ther1993 Sep 01; 266
AB  - 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.