Stereoselective metabolism of mexiletine in Chagasic women with ventricular arrhythmias

Following a week of racemic mexiletine HCl at 200 mg tid (2×100 mg capsules), stereoselective aliphatic hydroxylation was studied in eight Chagasic women with chronic ventricular arrhythmias (52–67 yrs) with no history of renal or hepatic diseases. Blood samples were collected at dose interval up to 24 h of drug administration. Plasma concentrations of R(−) and S(+) mexiletine (MEX) and its metabolite hydroxymethylmexiletine (HMM) were determined by HPLC after derivatization with chiral reagent. The differences between R(−) and S(+) enantiomers were compared by paired t-test. Results are mean (95% CI). The following differences (p<0.05) between R(−) and S(+) enantiomers, respectively, were found: MEX AUCss0−8 2.34 (1.84–2.85) vs 2.55 (1.97–3.13) μg.ml−1.h−1; MEX CL/f 11.27 (7.77–14.77) vs 10.46 (7.18–13.74) ml.min−1.Kg−1; HMM Cmax 38.26 (24.3–52.22) vs 16.73 (10.1–23.29)ng.ml−1; HMM Tmax 4.71 (2.67–6.76) vs 3.29 (1.24–5.33) h and HMM AUCss0–8 253.50 (165.39–341.61) vs 103.70 (69.51–137.90)ng.ml−1.h−1. The AUCss0–8 ratio R(−)/S(+) for MEX was 0.93 (0.87–0.98) while for HMM was 2.50 (2.16–2.85). Distribution of MEX and HMM enantiomers were not significantly different. In this study we demonstrate that kinetic disposition of mexiletine exhibits stereoselectivityin vivo and that aliphatic hydroxylation is favored for R(−) mexiletine in Chagasic women with ventricular arrhythmias.