雷贝拉唑肝、肠首过效应研究

目的研究雷贝拉唑在大白兔体内经十二指肠、门静脉与外周静脉等不同方式及不同剂量给药时的药代动力学,并探讨肠道、肝脏首过效应分别对其生物利用度的影响。方法在建立新西兰大白兔肠道血管通路模型基础上,从十二指肠(ID1.5、3、6mg·kg-1)、门静脉(PV1.5、3mg·kg-1)及耳缘静脉(V0·75、1.5、3mg·kg-1)不同途径、不同剂量给药,各时间点取血,高效液相色谱法检测雷贝拉唑血药浓度,评价其药代动力学,并计算生物利用度及肠道与肝脏提取率。结果随给药剂量增大,ID、PV、V给药时AUC0-t(mg·L-1·h)、AUC0-∞(mg·L-1·h)、Cmax(mg·L-1)均随剂量增大而升高(P<0.05),但Tmax(h)、T21(h)等参数无差异(P>0.05),CL(L·h-1·kg-1)则随给药剂量增加而降低(P<0.05)。经十二指肠给药1.5mg·kg-1时生物利用度为7.4%,3mg·kg-1时生物利用度为8.3%,肝脏提取率分别为84.8%、81.2%,肠道提取率分别为51.2%、56%。结论在大白兔各种给药方式时雷贝拉唑AUC0-t(mg·L-1·h)、AUC0-∞(mg·L-1·h)及Cmax(mg·L-1)均存在明显剂量依赖性;十二指肠给药时生物利用度较低,并且不呈剂量依赖性,原因主要为在肠道与肝脏经历较广泛的首过代谢。

Hepatic and intestinal first-pass effects of rabeprazole in rabbits

Aim To investigate the pharmacokinetics of rabeprazole after intravenous,intraportal and intraduodenal administration at various doses and to clarify the impact of hepatic and intestinal first-pass effects to bioavailability of rabbits.Methods By developing an in vivo intestinal and vascular access-ported(IVAP) rabbit model,doses of 0.75,1.5,3 mg·kg-1(intravenous);1.5,3 mg·kg-1(intraportal) and 1.5,3,6 mg·kg-1(intraduodenal) were administered to rabbits respectively.Serial blood samples were collected at various time points,and plasma drug concentration was analyzed by a high-performance liquid chromatography fluorescence method.Then the pharmacokinetic parameters were evaluated and absolute bioavailability and hepatic and intestinal extraction ratios were calculated.Results The pharmacokinetic parameters AUC0-t、AUC0-∞ and Cmax increased significantly with increasing doses of intravenous,intraportal and intraduodenal administration respectively (P<0.05),and there were no differences in elimination half-life at any dose in intravenous,intraportal and intraduodenal administration respectively(P>0.05).But the clearance decreased significantly with increasing doses(P<0.05). The absolute bioavailability of rabeprazole after intraduodenal administration was 7.4% and 8.3% at the dose of 1.5 mg·kg-1 and 3 mg·kg-1 respectively;the hepatic extraction ratio was 84.8% and 81.2%,and the intestinal extraction ratio was 51.2% and 56% at the dose of 1.5 and 3 mg·kg-1,respectively.Conclusions AUC0-t、AUC0-∞ and Cmax were dose-dependent at intravenous,intraportal and intraduodenal administration in rabbits.The bioavailability of rabeprazole was low at the intraduodenal administration,and was not dose-dependent. The major reason could be rabeprazole undergoing considerable hepatic and intestinal first-pass effects.