Tissue distribution of mexiletine enantiomers in rats

1. The kinetics of distribution of the enantiomers of mexiletine were studied in various tissue (heart, brain, lungs, liver, kidneys and fat) in male Sprague-Dawley rats after administration of a single i.v. dose (10 mg/kg) of racemic mexiletine. 2. The pharmacokinetic parameters calculated from the serum data showed a 32% greater systemic clearance (162 ml/min per kg vs 123 ml/min per kg) and a 22% greater steady-state volume of distribution (9.0 l/kg vs 7.4 l/kg) for R(-)-mexiletine relative to the S(+)-enantiomer. However, the terminal elimination half-lives of the enantiomers (1.4 and 1.3 h for R(-)- and S(+)-mexiletine, respectively) did not exhibit stereoselectivity. 3. Maximum tissue concentrations of the enantiomers were observed at 5 min after dosage in all tissues studied. Stereoselective uptake was evident only in the liver tissue and was 2.4-fold greater for S(+)-mexiletine. High tissue/serum ratios (greater than 20 for both enantiomers) were observed in lungs, brain and kidneys. The cardiac concentrations of R(-)- and S(+)-mexiletine were 8- and 7-fold those of serum, respectively. 4. The results demonstrate that the uptake of mexiletine enantiomers into the target tissue (heart) is not stereoselective. However, the relatively high brain accumulation of the enantiomers may be related to the CNS side-effects commonly associated with mexiletine therapy.