| Summary: | Mexiletine is a relatively new class IB antiarrhythmic agent, similar in structure and pharmacological effects to lidocaine. It is effective mainly against ventricular arrhythmias and can be administered by the oral route, mexiletine is a chiral drug which is used clinically as the racemic mixture. The enantiomers of numerous chiral drugs have been shown to differ in their disposition in the body due to their stereoselective pharmacodynamic and/or pharmacokinetic properties. The relative antiarrhythmic potencies of the individual enantiomers of mexiletine have not been studied, nor have their pharmacokinetics been properly elucidated. Thus, the present study was aimed at developing a highly sensitive and stereoselective assay for mexiletine enantiomers which will be utilized to study their pharmacokinetics and in vitro serum protein binding.
A high-performance liquid-chromatographic assay was developed using the Pirkle[sup R] ionic chiral stationary phase. The enantiomers were resolved as their 2-naphthoyl derivatives. The HPLC mobile phase consisted of 5.5% 2-propanol in hexane and was delivered at a flow rate of 1.4 mL/min. Detection of the enantiomeric derivatives was accomplished with a fluorescence detector [230 nm (Ex) and 340 nm (Em)]. Recovery of the enantiomers from plasma after
pH adjustment to above 12 was found to be substantially low
and stereoselectively in favour of the S(+)-enantiomer when
compared with their recovery from water. This was attributed
to a greater plasma protein binding of the R(-)-isomer
despite the high plasma pH. Recovery was improved (83%),
and the natural enantiomeric ratio restored by precipitation
of the plasma proteins with barium hydroxide/zinc sulfate.
Linear calibration curves (r² >0.999) were obtained in
plasma over the concentration range 5 to 750 ng/mL for each
enantiomer. Similar correlations (r >0.999) were obtained in saliva from 10 to 1,500 ng/mL and in urine from 0.25 to 7.5 ug/ml and 10 to 500 ng/ml. The inter- and intra-assay coefficients of variation were less than 4% for all the biological fluids. The minimum detectable quantity of each enantiomer in plasma was 5 ng/mL at a signal-to-noise ratio of 5:1, representing 100 pg injected onto the column.
Protein binding of the enantiomers was determined with serum from five healthy male subjects. The mean percent free fraction of R(-)-mexiletine, 19.80 ± 2.64% was significantly (P<0.001) less than that of S(+)-mexiletine, 28.32 ± 1.45%. Binding was independent of concentration over the therapeutic range.
Five healthy male subjects (same as above) were given 300 mg of (±) -mexi letine hydrochloride (capsules) orally. The plasma concentration-time data were analyzed by AUTOAN and NONLIN computer programs. The enantiomer kinetics were best described by a triexponential function in three of the five subjects and a biexponential function in the remaining two. There was no statistically significant difference in the absorption and distribution rate constants, peak plasma concentrations, time to peak plasma concentrations and plasma AUCs of the enantiomers. Bioavailability of the enantiomers was not determined due to lack of approval from the Health Protection Branch (Canada) to administer intravenous (±) -mexiletine to healthy volunteers. The terminal elimination half-life from plasma data for R (-)-mexiletine, 9.1 ± 2.9 hours, was significantly (P<0.02) less than that for the S( + )-isomer, 11.0 ± 3.8 hours. The cumulative urinary excretion of S(+)-mexiletine was 9.14 ± 3.07%, which was significantly (P<0.01) greater than that of R(-)-mexiletine, 7.40 ± 2.40%. Renal clearance of the enantiomers was consistent with cumulative urinary excretion, 0.72 ± 0.26 mL., min-1.Kg-1 and
0.61 ± 0.20 mL.min⁻¹.Kg⁻¹respectively (P<0.05).
The non-renal elimination rate constant (mainly metabolism)
was significantly (P<0.001) greater for R(-)-mexiletine, 0.0763 ± 0.0273 h⁻¹, than for the S( + )-iosmer, 0.0634 ± 0.0270 h⁻¹. The saliva AUCS were 18.2. ± 6.3 ug.mL ⁻¹.hr and 14.1 ± 5.0 ug. mL⁻¹.hr for
S(+)-mexiletine and the R(-)-isomer respectively (difference significant, P<0.01). The enantiomer concentration ratios (R/S) in the three biological fluids showed evidence of a cross-over [R(-)> S(+) to S(+)>R(-)] between 0-2 hours in urine and saliva and 8-10 hours in plasma. This indicated an apparent discrepancy in the cross-over time in plasma relative to urine and saliva. However, the free enantiomer concentration ratios in plasma were similar to the enantiomer ratios in urine and saliva.
Thus the disposition of mexiletine enantiomers in man is stereoselective with serum protein binding and metabolism favouring the R(-)-isomer. Renal elimination and salivary secretion, on the other hand, favour the S(+)-isomer. The similarity between the free enantiomer ratios in plasma, urine and saliva suggests that the stereoselective renal elimination and salivary secretion of the enantiomers are a reflection of their stereoselective protein binding. === Pharmaceutical Sciences, Faculty of === Graduate
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