基于药代动力学特征定量评估金丝桃素肝肠首过效应

Quantitative evaluation the hepatic and intestinal first pass effect of hypericin based on pharmacokinetic characteristics

目的:评价不同给药途径下金丝桃素(Hyp)大鼠体内药代动力学特征及定量评估其肝肠首过效应。方法:大鼠分别经十二指肠(id)和门静脉(ipv)置管建立给药模型,经id(100 mg·kg^(-1),200 mg·kg^(-1),400 mg·kg^(-1)),ipv(50 mg·kg^(-1),100 mg·kg^(-1),200 mg·kg^(-1)),外周静脉(iv,50 mg·kg^(-1),100 mg·kg^(-1),200 mg·kg^(-1))给予Hyp。高效液相色谱法测定血药浓度,采取浓度时间曲线下面积(AUC)计算Hyp生物利用度(BA)以及肝脏提取率(Eh)和肠道提取率(Ei)。结果:经id、ipv、iv给予不同剂量Hyp,其AUC值均随给药剂量升高而升高,剂量标准化后AUC值呈剂量非依赖性;AUC_(id)显著低于AUC_(ipv)和AUC_(iv)(P<0.05),而AUC_(ipv)和AUC_(iv)差异无统计学意义。各给药途径不同剂量间T_(1/2)和清除率差异无统计学意义。id给予100 mg·kg^(-1)和200 mg·kg^(-1)Hyp后,其BA分别为(4.53±0.6)%、(9.27±2)%,Eh分别为(17.89±4.82)%、(17.01±9.48)%,Ei为(94.49±1.73)%、(88.82±3.09)%。结论:经不同给药途径给予Hyp,其剂量标准化后的AUC值呈非剂量依赖性,增加药物剂量不能显著提高BA。Hyp经历显著首过效应,肠道是其首过效应主要发生部位。

Objective:To evaluate the pharmacokinetics characteristics of hypericin(Hyp)under different administration routes and quantitatively evaluate the hepatic and intestinal first-pass effect in rats.Methods:The rats were catheterized via duodenum(id)and portal vein(ipv).Different doses of Hyp were administered to rats via the id(100,200,400 mg·kg^(-1)),ipv(ipv,50,100,200 mg·kg^(-1))and iv port(50,100,200 mg·kg^(-1))respectively.The serum concentration of Hyp was determined by high performance liquid chromatography.The absolute bioavailability and hepatic and intestinal extraction ratio were calculated by the area under the plasma concentration-time curve(AUC).Results:The AUC values of Hyp with id,ipv and iv increased with the increase of drug dose.After dose normalization,AUC values did not show a dose-dependent manner.AUCid value was significantly lower than that of AUC_(ipv)and AUC_(iv)(P<0.05),while AUC_(ipv)and AUC_(iv)had no statistical significance.There was no significant difference in T_(1/2) and clearance rate among different dose routes.After 100 mg·kg^(-1)and 200 mg·kg^(-1)Hyp was administered via id port,the absolute bioavailability was(4.53±0.6)%and(9.27±2)%.The hepatic extraction ratios were(17.89±4.82)%,(17.01±9.48)%and the intestinal extraction ratios were(94.49±1.73)%,(88.82±3.09)%,respectively.Conclusion:The AUC value of Hyp was dose-independent after dose normalization via different administration routes,and the bioavailability of Hyp could not be significantly improved by increasing dose.Hyp underwent significant first pass effect,and intestinal tract was the main site of the first pass effect.