Resolution and Electrophysiological Effects of Mexiletine Enantiomers

Abstract

Abstract Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(–)- and S-(+)-mexiletine were resolved with an optical purity > 98 % (yield ∼ 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7–30 days after coronary ligation. R-(–)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0·5 mg kg−1, 1 after 8 mg kg−1); two animals died after 1 and 8 mg kg−1, respectively; one remained unchanged even at the highest dosage (16 mg kg−1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg−1); two died after 4 and 8 mg kg−1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg−1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0·5–16·0 mg kg−1). These results suggest that R-(–)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.