口服和静滴外消旋维拉帕米的药效学结合对映体药代动力学分析

EVALUATION OF PHARMACODYNAMICS COMBINED ENANTIOSELECTIVE PHARMACOKINETICS OF RACEMIC VERAPAMIL ADMINISTERED BY MOUTH AND INTRAVENOUS INFUSION

考察８名汉族男性健康志愿者口服８０ｍｇ和静滴５ｍｇ外消旋维拉帕米的心血管效应（心率、血压和ＰＲ间期），并结合对映体药代动力学分析其药效学特性。以三甲基－β－环糊精为手性选择剂，毛细管电泳法测定维拉帕米对映体血浆浓度。用药代动力学－药效学结合模型，即二房室模型加效应室，估算以维拉帕米总浓度和Ｓ－（－）－维拉帕米浓度对ＰＲ间期延长百分率的药效学参数。口服给药时，以维拉帕米总浓度估算的药效学参数Ｅｍａｘ（％），ＣＥ５０（μｇ·Ｌ－１），Ｋｅｏ和γ分别为４３．７±２１．１，６９．４±３０．３，３．６４±４．７和２．８５±２．０１；以Ｓ－（－）－维拉帕米估算的药效学参数分别为４７．７±２６．９，１４．３±８．５，５．２３±５．５和３．２４±１．８。静脉给药时，以维拉帕米总浓度估算的药效学参数分别为３５．２±１３．３，２９．７±１２．９，６．３６±３．２和２．２８±１．６；以Ｓ－（－）－维拉帕米估算的药效学参数分别为３５．７±１７．２，１３．４±８．４１，７．１３±３．４２和２．５２±１．５２。因此，在不同给药途径下或对映体比率的个体间差异较大时，以Ｓ－（－）－维拉帕米浓度与效应拟合药效学参数，较总浓度更有临床意义。

Effects of cardiovascular functions (blood pressure, resting heart rate and PR interval prolongation) and pharmacodynamics of racemic verapamil (VPM) administrated by oral and intravenous infusion were evaluated in eight healthy Chinese male volunteers. Plasma concentrations of the enantiomers of verapamil(VPM) were determined by capillary zone electrophoresis using trimethyl--cyclodextrin as chiral selector. Pharmacodynamic parameters of total VPM and S-(-)-VPM concentrations to percentage of PR interval prolongations were predicted using pharmacokinetic pharmacodynamic combined model at nonsteady-state after single dosages. The pharmacodynamic parameters, Emax(%), CE50(gL-1), Keo and of VPM after oral dosage were 43.721.1, 69.430.3,3.644.7 and 2.852.01 respectively;The pharmacodynamic parameters, Emax(%), CE50(gL-1), Keo and of S-(-)-VPM after oral administration were 47.726.9,14.38.5,5.235.5 and 3.241.8 respectivly. The pharmacodynamic parameters, Emax(%), CE50(gL-1), Keo and of VPM after Acknowledgements The author would like to acknowledge Dr. Longstreth (Searle Co., Skokie, IL,USA ) for kindly providing the standards of R-(+)-VPM(HCL,S-(-)-VPM(HCL,()NVPMHCL, R-(+)-NVPMHCL and S-(-)-NVPMHCL. intravenous infusion were 35.213.3,29.712.9,6.363.2 and 2.281.6 respectively; The pharmacodynamic parameters , Emax(%), CE50(gL-1), Keo and of S-(-)-VPM after intravenous infusion were 35.717.2,13.48.41,7.133.422.521.52 respectively. Thus, It is of more significance for clinical therapy to fit pharmacodynamic parameters with S-(-)-VPM concentration replacing total VPM concentration as administrated by different route.