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.

Preparative high-performance liquid chromatography and preparative thin-layer chromatography isolation of tocainide carbamoyl-O-beta-D-glucuronide: structural characterization by gas chromatography-mass spectrometry and fast atom bombardment-mass spectrometry.

Tocainide carbamoyl-O-beta-D-glucuronide, a major urinary metabolite of the antiarrhythmic drug tocainide [2-amino-N-(2',6'-xylyl)propanoxylidide], was isolated by preparative-TLC and preparative-HPLC. The isolated glucuronide was hydrolyzed in sodium hydroxide (pH greater than 12) to 3-(2',6'-xylyl)-5-methylhydantoin. This hydantoin product was also identified when tocainide was reacted with urea in urine. Structural characterization of the isolated tocainide glucuronide was carried out using GC-MS of the permethylated derivative. The molecular ion of the permethylated glucuronide was not observed, but ion fragments at m/z 232(244), 277(288), and 334(349) were found to correspond to the postulated novel carbamoyl ester structure of the permethylated (perdeuteromethylated) glucuronide. Structural evidence for the underivatized tocainide glucuronide was obtained using fast atom bombardment-MS. The [M + H]+ ion at m/z 413 was observed. Characteristic sodium ion adducts [M + Na]+ and [M-H + 2Na]+ were also observed at m/z 435 and 457, respectively.

A gas chromatographic assay for tocainide carbamoyl-O-beta-D-glucuronide:quantitation of the base hydrolyzed product, 3-(2',6'-xylyl)-5-methylhydantoin.

Quantitation of tocainide carbamoyl-O-B-D-glucuronide, a major metabolite of the antiarrhythmic agent, tocainide, was previously reported using sodium hydroxide hydrolysis (pH greater than 12) of the glucuronide followed by gas chromatographic analysis of the hydrolyzed product, 3-(2',6'-xylyl)-5-methylhydantoin. In this investigation, the hydantoin was found to undergo rapid degradation during base hydrolysis of the tocainide glucuronide. The hydantoin was synthesized and its hydrolysis in sodium hydroxide (pH greater than 12) was found to follow first-order kinetics with an estimated half-life of 24.6 minutes. This spontaneous and rapid degradation of the hydantoin during hydrolysis of the tocainide glucuronide may result in underestimation of the hydantoin. To correct for the degradation of the hydantoin, a gas chromatographic assay with a timed, base-hydrolysis calibration protocol was designed. To demonstrate the applicability of this assay, the elimination kinetics of tocainide and the tocainide carbamoyl glucuronide were studied in three healthy male volunteers after a single 200 mg oral dose of tocainide hydrochloride. From urine data, the elimination half-life of tocainide was approximately 15.5 hours. The urinary excretion half-life of the tocainide carbamoyl glucuronide was approximately 13.8 hours.