盐酸多奈哌齐在家兔体内的立体选择性药动学研究

 目的建立高效毛细管电泳法测定家兔血浆样品中盐酸多奈哌齐对映体,并用于口服给药后的立体选择性药动学研究。方法血浆中加入内标L-酒石酸布托菲诺并经碱化后以异丙醇-正己烷(3∶97)提取血浆样品,采用未涂层石英毛细管柱(70 cm×50μm),以25 mmol·L^-1的磷酸-三乙胺(pH 2.5)为运行缓冲液,25 g·L^-1磺化β-环糊精为手性添加剂,进样电压为-20kV,进样时间为15 s,运行电压为-20 kV,对家兔血浆样品中盐酸多奈哌齐对映体进行测定。并用3P97程序计算两者的药动学参数。结果测得血浆样品中多奈哌齐两对映体在0.1～5 mg·L^-1内均呈良好的线性关系。家兔口服30 mg·kg^-1盐酸多奈哌齐后两对映体在家兔体内均符合二房室模型,经统计学t检验,两对映体的ρ_max之间有非常显著性差异(P<0.01),AUC_0-48及AUC_0-∞之间有显著性差异(P<0.05),而两对映体的t_max,t_1/2,MRT之间则无显著性差异(P>0.05)。结论两对映体的家兔体内代谢过程存在立体选择性。

Studies on Stereoselective Pharmacokinetics of Donepezil Hydrochloride (E2020) in Rabbit

OBJECTIVE To develop a capillary electrophoresis(CE) method for the determination of donepezil enantiomers in plasma,and to investigate its stereoselective pharmacokinetics in rabbit.METHODS Alkalized plasma was extracted by isopropanol-n-hexane(3∶97) and L-butefeina was used as the internal standard.Enantioresolution was achieved using 25 g·L^-1 sulfated-β-cyclodextrin in 25 mmol·L^-1 triethylammonium phosphate solution(pH 2.5) as chiral selector on the uncoated fused-silica capillary column(70 cm×50 μm).RESULTS The linear calibration curves of the enantiomers were obtained in the concentration range of(0.1～5 mg·L^-1).After an oral administration of 30 mg·kg^-1 donepezil hydrochloride to 6 rabbits,the main pharmacokinetic parameters of R(-)-donepezil and S(+)-donepezil were as follows:t_max(1.09±0.54) and(1.35±0.48) h;t_1/2(31.60±19.04) and(24.60±18.81)h;ρ_max(2.08±0.59) and(1.22±0.22) mg·L^-1;AUC_0-48(18.76±7.11) and(9.42±2.92) mg·h·L^-1;AUC_0-∞(21.74±22.01) and(10.79±3.87) mg·h·L^-1,MRT(31.25±22.48) and(18.25±16.79)h.The pharmacokinetic profiles were fitted with a two-compartment model by 3P97 software.There were significant differences on ρ_max(P<0.01),AUC_0-48 and AUC_0-∞(P<0.05) between the enantiomers.CONCLUSION The pharmacokinetics of E2020 enantiomers in rabbit exhibits stereoselectivity.