普罗帕酮两对映体间的药动学和药效学相互作用研究

采用随机、交叉、双盲法给予8名健康受试者多次剂量（150mg,q6h)来考察普罗帕酮三种片剂（消旋体、左旋体、右旋体）和安慰剂,立体选择性高效液相色谱法测定稳态时一个给药间隔（0－6h)的血浆中两对映体浓度,心电图同时记录PR、QRS和QTc间隙并测试最大运动心率HRmax及血压变化情况,TopFit软件拟合参数。结果表明,三种制剂的平均驻留时间MRT及峰时Tmax无差别。给予消旋体片剂后,右旋体的清除率C1明显低于左旋体（P＜0.05),单纯给予对映体时,右旋体的清除率则大于左旋体（P＜0.001)。左旋体的存在提高了右旋体的血浆浓度,增强了β-受体阻断作用。普罗帕酮在人体内消除存在立体选择性,且两对映体产生了药效学上的相互作用。临床应用消旋体可不作剂量调整,但对某些患者应慎重使用。

The Interaction Between both Enantiomers of Propafenone in Pharmacokinetics and Pharmacodynamics

Eight healthy male subjects receivedtreatment in a randomized, cross-over, double-blind study R/S-,S- and R- propafenone inmultiple doses (150 mg each every 6 h) and placebo. The steady state plasma concentrationsof both enantiomers of propafenone in the last dose interval were measured bystereoselective HPLC method and ECG, blood pressure and heart rate were monitored.Pharmacokinetic parameters were calculated by the TopFit programe. The data indicated thatmean residence time(MRT) and time to reach peak concentrations(Tmax) of S- andR-propafenone were similar and independent of the administered agent. When the racematewas given, the clearance of S- propafenone was lower than that of R-propafenone(P<0.05). When the pure enantiomer was administrated alone, the clearance ofS- propafenone was higher than that of R- propafenone(P<0.001). The plasmaconcentrations of S- propafenone were higher in the presence of R- propafenone and β- adrenoceptor blocking action ofS- propafenone was affected by the presence of its optical antipode. A stereoselectiveelimination of propafenone was observed in chinese subjects. Enantiomer/enantiomerinteraction in pharmacokinetics and pharmacodynamics was also occurred. Dosagemodifications are probably not required in patients receiving racemic propafenone, but itmust be used cautiously for some treatment of arrhythmia.