Stereoselective disposition of mexiletine in man

The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 +/- 0.12 (s.d.) and 0.80 +/- 0.21, respectively. Urinary excretion of mexiletine conjugates consisted mainly of the R-(-)-enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 +/- 3.10. Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 +/- 0.48 and the renal clearance of the R-(-)-enantiomer was significantly higher (P less than 0.02) than that of the S-(+)-enantiomer.