Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats
Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats
复制标题
肝脏和肠道首过效应的差异有助于钩藤碱和异钩藤碱差向异构体在大鼠体内的立体选择性药代动力学
DOI：
10.1016/j.jep.2017.07.039
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发表时间：
2017
影响因子：
5.4
通讯作者：
Feng Feng
中科院分区：
文献类型：
--
作者：
Wang Xin;Zheng Mei;Liu Jia;Huang Zhifeng;Bai Yidan;Ren Zhuoying;Wang Ziwen;Tian Yangli;Qiao Zhou;Liu Wenyuan;Feng Feng
民族药理学相关性钩藤Uncaria rhynchophylla（Miq.）MIQ.来自Havil.，是一种用于传统中药治疗心血管和中枢神经系统疾病的植物。钩藤碱（Rhynchophylline，RIN）和异钩藤碱（Isorhynchophylline，IRN）是从乌藨子中分离得到的主要生物碱，是乌藨子中的一对差向异构体。钩藤碱具有多种药理作用。我们前期的研究表明，这些差向异构体口服后的药代动力学存在立体选择性;本研究的目的是阐明RIN和IRN在大鼠体内立体选择性药代动力学特征的机制。材料和方法总（F），采用门静脉插管大鼠，按照不同给药途径（静脉内、门静脉内和十二指肠内）测定每种差向异构体的肝脏（Fh）和肠道（Fa·Fg）生物利用度，以评估肝脏和肠道在立体选择性药代动力学中的个体贡献。然后分别与大鼠肝微粒体、小肠S9和胃肠道内容物溶液体外孵育，评价两种差向异构体在肝和肠中首过代谢的差异。同时，采用在体单向肠灌流法，观察P-糖蛋白（P-gp）抑制剂维拉帕米对肠粘膜通透性和P-gp外排的影响。RIN在不同pH值下的构型相互转换以及经粪便和尿液的排泄也进行了检查。结果药代动力学数据显示，RIN的总生物利用度是IRN的5.9倍（23.4%比4.0%）。RIN的肝脏利用度是IRN的4.6倍（46.9% vs. 10.3%），而RIN的肠道利用度（48.1%）与IRN（42.7%）相当。肠灌流实验表明，IRN的肠通透性高于RIN，且与维拉帕米共灌可影响RIN的吸收过程，但IRN无此作用。相反，IRN在大鼠肝微粒体中的代谢速率显著快于RIN，导致口服给药后IRN的全身暴露量较低。胃肠道内的降解和两种差向异构体之间的差向异构化也存在，但贡献较小。此外，这两个差向异构体通过粪便和尿液的排泄可以忽略不计。ConclusionsTaken在一起，不同的首过代谢在肝脏中的RIN和IRN的立体选择性药代动力学的主要因素。
Ethnopharmacological relevanceUncaria rhynchophylla(Miq.) Miq. ex Havil., is a plant species used in traditional Chinese medicine to treat cardiovascular and central nervous system diseases. Rhynchophylline (RIN) and isorhynchophylline (IRN), a pair of epimers, are major alkaloids isolated fromU. rhynchophyllaand exhibit diverse pharmacological effects. Our previous study demonstrated that the pharmacokinetics of these epimers existed stereoselectivity after oral administration; however, the specific mechanism remains unknown and merits investigation.Aim of the studyIn the present study, the aim was to elucidate the mechanism underlying stereoselective pharmacokinetic characteristics of RIN and IRN in rats.Materials and methodsThe total (F), hepatic (Fh) and intestinal (Fa·Fg) bioavailabilities of each epimer were measured using portal vein cannulated rats following different dosing routes (intravenous, intraportal and intraduodenal) to assess individual contributions of the liver and intestine in stereoselective pharmacokinetics. Then the differences of first-pass metabolism in the liver and intestine between two epimers were evaluated by in vitro incubation with rat liver microsomes, intestinal S9 and gastrointestinal (GI) content solutions, respectively. Meanwhile, the membrane permeability and efflux by P-glycoprotein (P-gp) were examined by in situ single-pass intestinal perfusion with and without P-gp inhibitor verapamil. The configurational interconversion at different pH values and the excretions via feces and urine were also examined.ResultsPharmacokinetic data showed that the total bioavailability of RIN was 5.9 folds higher than that of IRN (23.4% vs. 4.0%). The hepatic availability of RIN was 4.6 folds higher than that of IRN (46.9% vs. 10.3%), whereas the intestinal availability of RIN (48.1%) was comparable to that of IRN (42.7%). In addition, intestinal perfusion showed that IRN possessed higher intestinal permeability than RIN and co-perfusion with verapamil could affect absorption process of RIN but not IRN. Conversely, the metabolism rate of IRN in rat liver microsomes was significantly faster than that of RIN, resulting in a lower systemic exposure of IRN after oral administration. The degradation in GI lumen and epimerization between two epimers also existed but had small contributions. Additionally, the excretions of both epimers via feces and urine were negligible.ConclusionsTaken together, different first-pass metabolism in the liver was the major factor responsible for the stereoselective pharmacokinetics of RIN and IRN.