Stereoselective metabolism of mexiletine in Chagasic women with ventricular arrhythmias

Abstract

Following a week of racemic mexiletine HCl at 200 mg tid (2x100 mg capsules), stereoselective aliphatic hydroxylation was studied in eight Chagasic women with chronic ventricular arrhythmias (52-67 yrs) with no history of renal or hepatic diseases. Blood samples were collected at dose interval up to 24 h of drug administration. Plasma concentrations of R(-) and S(+) mexiletine (MEX) and its metabolite hydroxymethylmexiletine (HMM) were determined by HPLC after derivatization with chiral reagent. The differences between R(-) and S(+) enantiomers were compared by paired t-test. Results are mean (95% CI). The following differences (p < 0.05) between R(-) and S(+) enantiomers, respectively, were found: MEX AUCss(0-8) 2.34 (1.84-2.85) vs 2.55 (1.97-3.13) microg.ml(-1) x h(-1); MEX CL/f 11.27 (7.77-14.77) vs 10.46 (7.18-13.74)ml.min(-1).Kg(-1); HMM Cmax 38.26 (24.3-52.22) vs 16.73 (10.1-23.29)ng.ml(-1); HMM Tmax 4.71 (2.67-6.76) vs 3.29 (1.24-5.33) h and HMM AUCss(0-8) 253.50 (165.39-341.61) vs 103.70 (69.51-137.90)ng.ml(-1).h(-1). The AUCss(0-8) ratio R(-)/S(+) for MEX was 0.93 (0.87-0.98) while for HMM was 2.50 (2.16-2.85). Distribution of MEX and HMM enantiomers were not significantly different. In this study we demonstrate that kinetic disposition of mexiletine exhibits stereoselectivity in vivo and that aliphatic hydroxylation is favored for R(-) mexiletine in Chagasic women with ventricular arrhythmias.

Stereospecific synthesis of “para‐hydroxymexiletine” and sodium channel blocking activity evaluation

“…In vitro studies, performed with human liver microsomes, demonstrated that aliphatic hydroxylation is predominant for ( -)-(R)-Mex, whereas aromatic hydroxylation is favored for the (+)-(S)-enantiomer. 10 As far as the aliphatic hydroxylation is concerned, these data have been confirmed in vivo, 6,7 while the difference between (S)-and (R)-PHM plasma concentrations was less pronounced, the latter slightly predominating. 7 Furthermore, data also suggest that the metabolic conversion of the hydroxylated metabolites into the corresponding glucuronides is enantioselective, determining the preferential elimination of ( -)-(R)-Mex.…”

“…9,16 Following a personal communication of Danneberg and Haselbarth to Levy-Prades et al, 12 the inactivity of Mex metabolites consolidated in the mindset of scientists devoted to the study of Mex disposition. 6,16,17 Indeed, only recently Kamei 18 studied the antinociceptive effects of the enantiomers of HMM in streptozotocineinduced diabetic mice using the tail-pinch and the tail-flick test; HMM did not produce a significant dose-dependent inhibition of the tail-pinch response. Thus, up to now, no clear evidence of the inactivity of PHM is available.…”

Enantioselective analysis ofN-hydroxymexiletine glucuronide in human plasma for pharmacokinetic studies

“…The hydroxymetabolites were added at therapeutic concentrations as reported in a previous study. 8 Linearities were determined using least-square regression analysis of peak-height versus drug concentration in plasma. Correlation coefficients of the standard curves were >0.99 for six concentrations of (+)-S-MEX and (−)-MEX in the range 50-1000 ng/ml ( Table 2).…”

“…8 The method was considered linear up to the highest MEX concentration studied that showed a linear relationship with the response of the detector.…”

Facile entry to (?)-(R)- and (+)-(S)-mexiletine

“…1a is a more potent blocker of sodium currents of frog adult skeletal muscle fibers, 3,4 while 1b is more effective than 1a as an inhibitor of clorgyline-resistant amine oxidase (CRAO) 5 and in the treatment of allodynia. 6 A complex pattern of stereoselectivity in the pharmacokinetics of 1a and 1b in rats and humans has been disclosed by a number of studies revealing differences in the respective areas under the serum concentration-time curve (AUC S , 1a < 1b), 7,8 plasma elimination half-lives (t 1/2 , 1a < 1b), 7,8,9 aliphatic hydroxylation, 10,11 aromatic hydroxylation, 11,12 and conjugation 13,14 (1a being more extensively metabolized than 1b), cumulative urinary excretion (renal clearance of 1a is greater than 1b), 8,9 apparent volumes of distribution (V d , 1a < 1b), 9 and liver uptake (maximum liver concentration of 1b is greater than 1a). 15 The question whether mexiletine enantioselective disposition, which favors the elimination of 1a, may partially compensate the clinical action of the latter remains unanswered.…”