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UBC Theses and Dissertations

Stereoselective HPLC analysis, pharmacokinetics, tissue distribution and pharmacodynamics of mexiletine enantiomers Igwemezie, Linus Nnamdi


Mexiletine [(2',6'-dimethylphenoxy)-2-amino propane] is a class 1 antiarrhythmic agent with a similar chemical structure and electrophysiological effects to those of lidocaine. It is a chiral drug which is used clinically in the racemic form (i.e. 50:50 ratio of two enantiomers). This thesis describes the stereoselective HPLC analysis, pharmacokinetics, tissue distribution and pharmacodynamics of mexiletine enantiomers. The development of a highly sensitive and stereoselective HPLC assay for mexiletine enantiomers, using 2-anthroyl chloride as a derivatization reagent, was attempted. The synthesis and characterization of the acid chloride was successfully carried out. The 2-anthroyl derivatives of the enantiomers were resolved on a Pirkle[formula omitted] ionic (phenyl glycine) chiral column using a mobile phase of ethyl acetate/2-propanol/Hexane (4:6:90). Detection was accomplished by fluorescense (ex = 270 nm, em = 400 nm) with a lower limit of 0.5 ng/ml. However, there was an interfering peak coeluting with S(+)-mexiletine which could not be resolved. This precluded the use of the assay for the proposed pharmacokinetic and pharmacodynamic studies. A previously developed stereoselective HPLC method, with 2-naphthoyl chloride as a derivatization reagent, was subsequently used. The in vitro protein binding of mexiletine enantiomers was examined with human serum, lipoprotein deficient serum, albumin and α[formula omitted]-acid glycoprotein. The binding of the enantiomers to human serum was moderate (45 to 50%) within the therapeutic range of mexiletine. This binding was due, mainly, to albumin and α[formula omitted]-acid glycoprotein. The free fractions of the enantiomers decreased significantly (P<0.05) as pH was increased from 7.0 to 8.0. Stereoselective binding was apparent at pH 8.0 such that the free fraction of S(+)-mexiletine was significantly (p<0.05) greater than that of the R(-)-enantiomer. However, stereoselective binding was not observed at physiological pH (≈ 7.4). These results indicated that the serum binding of mexiletine enantiomers is pH-dependent. Binding was not concentration-dependent, nor was there any competitive binding interaction between the enantiomers, within the therapeutic range. Scatchard analysis of the binding data obtained with serum and albumin both showed the presence of 2 classes of binding sites. A high affinity, low capacity site and a low affinity, high capacity site. In contrast, α[formula omitted]-acid glycoprotein showed only 1 class of binding sites and this was a high affinity, low capacity site. Pharmacokinetic and tissue distribution studies in rats following the administration of racemic mexiletine (10 mg/kg) indicated extensive tissue uptake and rapid elimination of the enantiomers. R(-)-Mexiletine showed a 32% greater systemic clearance (161.8 ml/min/kg vs 122.9 ml/min/kg) than the S(+)-enantiomer. The steady state-volume of distribution was also greater for the R(-)-enantiomer (9.0 L/kg vs 7.4 L/kg), while the elimination half-lives of the enantiomers (1.4 and 1.3 h for R(-)- and S(+)-mexiletine, respectively) were not different. Maximum tissue concentrations were observed at 5 min in all the tissues studied (heart, brain, lung, kidney, liver and fat). These concentrations were not significantly different, except for the liver tissue where a 2.4-fold greater concentration of the S(+)-enantiomer was found. High tissue/serum ratios (>20) were observed for each enantiomer in the brain, lungs and kidneys. The brain accumulated 3-fold the heart concentrations of the enantiomers. Pharmacodynamic studies on the relative antiarrhythmic effects of racemic mexiletine and its enantiomers were carried out using electrical and ischaemia-induced arrhythmias in rats. Racemic mexiletine and its enantiomers significantly (P<0.05) increased VFT and ERP. However, the differences between the effects of the 3 drugs on these variables were not statistically significant. R,S-, S(+)- and R(-)-mexiletine caused significant bradycardia and PR prolongation in both pentobarbitone anaesthetized and conscious rats. These effects of the drugs were also not significantly different from each other. In the ischaemic conscious rats, the 3 drugs did not significantly reduce the incidence of VT and VF, the number of PVCs nor the "arrhythmia score" when compared to saline (control). Racemic mexiletine and its enantiomers produced comparable CNS toxicity in the conscious rats.

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