Lanchote V L, Cesarino E J, Santos V J, Moraes Júnior A V, Zanardi A M, Santos S R
Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
Eur J Drug Metab Pharmacokinet. 1998 Apr-Jun;23(2):259-66. doi: 10.1007/BF03189349.
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.
在8名患有慢性室性心律失常（年龄52 - 67岁）且无肾病史或肝病史的恰加斯病女性患者中，给予消旋盐酸美西律200 mg每日三次（2粒100 mg胶囊），持续一周后，研究其立体选择性脂肪族羟基化作用。在给药后长达24小时的剂量间隔采集血样。用手性试剂衍生化后，通过高效液相色谱法测定R(-)和S(+)美西律（MEX）及其代谢物羟甲基美西律（HMM）的血浆浓度。通过配对t检验比较R(-)和S(+)对映体之间差异。结果为均值（95%可信区间）。分别发现R(-)和S(+)对映体之间存在以下差异（p < 0.05）：MEX的AUCss(0 - 8)为2.34（1.84 - 2.85）对2.55（1.97 - 3.13）μg·ml⁻¹·h⁻¹；MEX的CL/f为11.27（7.77 - 14.77）对10.46（7.18 - 13.74）ml·min⁻¹·kg⁻¹；HMM的Cmax为38.26（24.3 - 52.22）对16.73（10.1 - 23.29）ng·ml⁻¹；HMM的Tmax为4.71（2.67 - 6.76）对3.29（1.24 - 5.33）小时，以及HMM的AUCss(0 - 8)为253.50（165.39 - 341.61）对103.70（69.51 - 137.90）ng·ml⁻¹·h⁻¹。MEX的AUCss(0 - 8)的R(-)/S(+)比值为0.93（0.87 - 0.98），而HMM的该比值为2.50（2.16 - 2.85）。MEX和HMM对映体的分布无显著差异。在本研究中，我们证明美西律的动力学处置在体内表现出立体选择性，并且在患有室性心律失常的恰加斯病女性中，脂肪族羟基化作用更有利于R(-)美西律。
