The phenomenon of enantioselectivity in the metabolism of mexiletine (MEX) conjugation was investigated in eight female patients with the arrhythmic form of chronic Chagas' heart disease treated with racemic mexiletine hydrochloride (two 100 mg capsules every 8 hr). Blood samples were collected up to 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 the concentrations of unchanged and total (unchanged + conjugated) MEX enantiomers. Total plasma MEX concentrations were analyzed by HPLC after enzymatic hydrolysis with beta-glucuronidase, the formation of diastereomeric derivatives with the chiral reagent N-acetyl-L-cysteine/o-phthalaldehyde, and fluorescence detection. The differences in the pharmacokinetic parameters of the enantiomers were evaluated by the paired t-test. The plasma concentrations 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 plasma concentration Cmax = 194.0 ng.ml-1 (154.3-233.7), time to maximum plasma concentration tmax = 1.4 hr (0.3-2.5), area under the plasma concentration versus time curve AUC0-24 = 2099.2 ng.h.ml-1 (1585.6-2612.6), elimination half-life t1/2 beta = 12.8 hr (9.9-15.6) and extent of conjugation of 31.6% (24.3-38.9%). The present data indicate stereospecific conjugation of (-)-(R)-N-hydroxymexiletine in the female patients with the arrhythmic form of Chagas' heart disease.