维拉帕米对映体在人体的药代动力学

目的： 考察维拉帕米(VPM)和去甲维拉帕米(NVPM)对映体的药代动力学特性。 方法： 8名汉族男性健康志愿者分别po外消旋VPM 80 mg和静滴5 mg，以三甲基-β-环糊精为手性选择剂，毛细管电泳法同时测定VPM和NVPM对映体的血浆浓度，用二房室开放模型拟合药-时曲线。结果： po VPM的R/S(AUC),R/S(CL)和R/S(C_max)比率分别为3.66±1.86，0.3±0.053和4.82±0.58；NVPM的R/S(C_max)和R/S(AUC)比率为2.58和2.36。iv VPM的R/S(AUC)，R/S(CL)和R/S(C_max)比率分别为1.04±0.29，1.01±0.3和1.36±0.12。R-(+)-VPM和S-(-)-VPM的绝对生物利用度为30.3±19和9.8±5.9。结论： VPM有较大的对映体特异性首过代谢，选择优对映体S-(-)-VPM为监测对象有利于临床合理使用外消旋VPM。

ENANTIOSELECTIVE PHARMACOKINETICS OF VERAPAMIL IN EIGHT HEALTHY CHINESE MALE VOLUNTEERS

AIM: To investigate the enantiospecific pharmacokinetics of verapamil (VPM) and its major metabolite, norverapamil (NVPM). METHODS: Eight healthy Chinese male volunteers were given an oral dose of 80 mg or an intravenous infusion dose of 5 mg of racemic VPM. Plasma concentrations of enantiomers of VPM and NVPM were simultaneously determined by capillary zone electrophoresis using trimethyl-β-cyclodextrin as chiral selector. The concentration-time curves were fitted as two compartment open model. RESULTS: The ratios of R/S(AUC), R/S(CL) and R/S(C_max) of VPM given orally were 3.66±1.86, 0.3±0.053 and 4.82±0.58, respectively; the ratios of R/S(C_max) and R/S(AUC) of NVPM were 2.58 and 2.36. The ratios of R/S(AUC), R/S(CL) and R/S(C_max) of VPM given by intravenous infusion were 1.04±0.29, 1.01±0.3 and 1.36±0.12, respectively. Plasma concentrations of NVPM were lower than the limit of quantitative detection. Absolute bioavailability of R-(+)-VPM and S-(-)-VPM were 30.3±19 and 9.8±5.9. R/S ratio of bioavailability is 3.09. CONCLUSION: Distinct stereoselective first-pass metabolism in healthy Chinese males were observed. As racemic VPM were administered by different route or the individual variation of enantioselectove pharmacokinetics of VPM were noticeable. It is significent to monitor the concentration of S-(-)-VPM for safety, rationality and effectiveness in clinical therapy.