Enantioselectivity in the metabolism of mexiletine by conjugation in female patients with the arrhythmic form of chronic Chagas' heart disease

The phenomenon of enantioselectivity in the metabolism of mexiletine (MEX) conjugation was investigated in eight female patients with the arrhythmic f orm of chronic Chagas' heart disease treated with racemic mexiletine hydroc hloride (two 100 mg capsules every 8 hr). Blood samples were collected up t o 24 hr after the administration of the morning dose, with discontinuation of the subsequent doses during the study period. Plasma concentrations of N -hydroxymexiletine glucuronide were calculated as the difference between th e concentrations of unchanged and total (unchanged + conjugated) MEX enanti omers. Total plasma MEX concentrations were analyzed by HPLC after enzymati c hydrolysis with beta-glucuronidase, the formation of diastereomeric deriv atives with the chiral reagent N-acetyl-L-cysteine/o-phthalaldehyde, and fl uorescence detection. The differences in the pharmacokinetic parameters of the enantiomers were evaluated by the paired t-test. The plasma concentrati ons of the (+)-(S)-MEX did not differ before and after enzymatic hydrolysis . The pharmacokinetic parameters calculated for (-)-(R)-N-hydroxymexiletine glucuronide are presented as means (95% confidence interval): maximum plas ma concentration C-max = 194.0 ng . ml(-1) (154.3-233.7), time to maximum p lasma concentration t(max) = 1.4 hr (0.3-2.5), area under the plasma concen tration versus time curve AUC(0-24) = 2099.2 ng . h . ml(-1) (1585.6-2612.6 ), elimination half-life t(1/2)beta = 12.8 hr (9.9-15.6) and extent of conj ugation of 31.6% (24.3-38.9%). The present data indicate stereospecific con jugation of (-)-(R)-N-hydroxymexiletine in the female patients with the arr hythmic form of Chagas' heart disease. Chirality 11:29-32, 1999. (C) 1999 W iley-Liss, Inc.