title: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: V L
authors.initials: VL
authors.lastname: Lanchote
authors.forename: E J
authors.initials: EJ
authors.lastname: Cesarino
authors.forename: V J
authors.initials: VJ
authors.lastname: Santos
authors.forename: A V
authors.initials: AV
authors.lastname: Moraes Júnior
authors.forename: A M
authors.initials: AM
authors.lastname: Zanardi
authors.forename: S R
authors.initials: SR
authors.lastname: Santos
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000097:blood* / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000378:metabolism*; D014355:Chagas Disease / Q000150:complications / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D008657:Metabolic Clearance Rate; D008801:Mexiletine / Q000097:blood* / Q000493:pharmacokinetics; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: D000889:Anti-Arrhythmia Agents; D008801:Mexiletine