PHARMACOKINETICS OF MEXILETINE ENANTIOMERS IN HEALTHY-HUMAN SUBJECTS - A STUDY OF THE IN-VIVO SERUM-PROTEIN BINDING, SALIVARY EXCRETION ANDRED-BLOOD-CELL DISTRIBUTION OF THE ENANTIOMERS

1. The disposition kinetics of serum free (unbound) and total mexileti ne enantiomers were studied in 12 healthy subjects following oral admi nistration of 200mg 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 concentrat ion of 217 +/- 69 ng/ml for R(-)-mexiletine was found to be significan tly greater than a mean of 197 +/- 56 ng/ml for S(+)-mexiletine. The m ean serum total R(-)-mexiletine concentrations were also found to be s ignificantly 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 mexi letine enantiomers, were not significantly different. 3. Comparative i n vitro serum protein binding of mexiletine enantiomers examined by ul trafiltration and equilibrium dialysis indicated a pH-dependent stereo selective binding of the enantiomers to serum proteins. A serum pH ran ging 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-fr ee mexiletine enantiomer area under the concentration-time curve ratio s of 6.10 +/- 2.82 and 7.49 +/- 3.48 for R(-)- and S(+)-mexiletine res pectively were found to be significantly different. The overall mean s aliva R(-)IS(+) enantiomer ratio of 0.89 +/- 0.02 (mean +/- SE) over 4 8h suggested a stereoselective disposition of the mexiletine enantiome rs in saliva. 5. The mean mexiletine red blood cells to serum-free dru g concentration ratios among 11 subjects studied were found to range f rom 0.6 to 1.4 for R(-)-mexiletine and from 0.6 to 1.8 for S(+)-mexile tine. 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 wi th an overall red blood cell mean R(-)/S(+)-mexiletine concentration r atio of 0.91 +/- 0.13 suggested a non-stereoselective and passive diff usion of the enantiomers into red blood cells. 6. The cumulative amoun ts of unchanged R(-)- and S(+)-mexiletine in the urine were found to b e 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(+)-mexi letine.