Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers.

1. The disposition kinetics of serum free (unbound) and total mexiletine enantiomers were studied in 12 healthy subjects following oral administration of 200 mg racemic mexiletine hydrochloride. The disposition of the enantiomers of mexiletine in urine, saliva, and red blood cells was also examined. 2. The mean peak serum total mexiletine concentration of 217 +/- 69 ng/ml for R(-)-mexiletine was found to be significantly greater than a mean of 197 +/- 56 ng/ml for S(+)-mexiletine. The mean serum total R(-)-mexiletine concentrations were also found to be significantly greater than those for S(+)-mexiletine during the first 6 h following drug administration. The oral absorption, as well as the rapid and the terminal disposition kinetic parameters between the mexiletine enantiomers, were not significantly different. 3. Comparative in vitro serum protein binding of mexiletine enantiomers examined by ultrafiltration and equilibrium dialysis indicated a pH-dependent stereoselective binding of the enantiomers to serum proteins. A serum pH ranging from 6.3 to 9.4 was found to correlate with serum protein binding of the enantiomers from approximately 30-80% respectively. Within the same serum pH range, the serum free drug R(-)/S(+) ratios were found to decrease from 1.0 to 0.7 respectively. At serum pH7.4, a mean serum free fraction of 0.57 +/- 0.7 and 0.56 +/- 0.6 were observed for R(-) and S(+)-mexiletine respectively. 4. The overall mean saliva/serum-free mexiletine enantiomer area under the concentration-time curve ratios of 6.10 +/- 2.82 and 7.49 +/- 3.48 for R(-)- and S(+)-mexiletine respectively were found to be significantly different. The overall mean saliva R(-)/S(+) enantiomer ratio of 0.89 +/- 0.02 (mean +/- SE) over 48 h suggested a stereoselective disposition of the mexiletine enantiomers in saliva. 5. The mean mexiletine red blood cells to serum-free drug concentration ratios among 11 subjects studied were found to range from 0.6 to 1.4 for R(-)-mexiletine and from 0.6 to 1.8 for S(+)-mexiletine. The overall mean ratios of 0.85 +/- 0.06 and 0.84 +/- 0.08 (mean +/- SE) over 48 h for R(-)- and S(+)-mexiletine respectively were both slightly but significantly different from unity. This data together with an overall red blood cell mean R(-)/S(+)-mexiletine concentration ratio of 0.91 +/- 0.13 suggested a non-stereoselective and passive diffusion of the enantiomers into red blood cells. 6. The cumulative amounts of unchanged R(-)- and S(+)-mexiletine in the urine were found to be variable among the 12 subjects with a mean percent urinary recovery of 3.49 +/- 3.35% for R(-)-mexiletine and 3.68 +/- 3.94% for S(+)-mexiletine.