Wu Rongrong, Xiao Zhiyong, Zhang Xiaorui, Liu Feng, Zhou Wenxia, Zhang Yongxiang
State Key Laboratory of Toxicology and Medical Countermeasures, Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, China.
Front Pharmacol. 2018 Mar 14;9:229. doi: 10.3389/fphar.2018.00229. eCollection 2018.
It is highly valuable to study the pharmacokinetics of herbal components under the pathological condition of liver dysfunction for safe and rational use of herbal medicines. In this study, the pharmacokinetic profiles of four effective lignans from , schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, were investigated in carbon tetrachloride (CCl)-intoxicated rats. The metabolism of the four lignans was also studied using microsomes from patients with advanced hepatocellular carcinoma. intestinal and hepatic perfusions were conducted to clarify the contributions from impairments of gut and liver on the pharmacokinetics of the four schisandra lignans in CCl-intoxicated rats. The metabolism in rat and human liver microsomes and transport in Caco-2 monolayer cell model were studied to reveal the key factors for the disposition of the four lignans. When SC alcoholic extract was orally administrated to CCl-intoxicated rat for a short term (4 days), the pharmacokinetics of four active SC lignans was significantly changed while its hepatotherapeutic effect was not obviously observed. The plasma concentrations of the four schisandra lignans were dramatically elevated compared with the control. The Cmax, AUC and MRT were all increased or prolonged significantly while parameter CLz/F was obviously reduced in rat pretreated with CCl. In hepatic perfusion study and liver microsomes incubation, it was found that the hepatic metabolism of the four lignans was markedly decreased mainly due to the activity reduction of multiple CYP450 isoenzymes involved the metabolism, which, eventually, might lead to the alternation of their pharmacokinetic profiles in CCl-intoxicated rats or patients with advanced hepatocellular carcinoma. The pharmacokinetic studies of SC components in pathological situation of liver dysfunction are expected to provide useful data for rational and safe application of SC preparations in clinic or further pharmacological and toxicological research.
为了安全合理地使用草药，研究肝功能不全病理状态下草药成分的药代动力学具有很高的价值。在本研究中，考察了五味子中四种有效木脂素，即五味子醇甲、五味子酯甲、脱氧五味子醇和γ-五味子醇在四氯化碳（CCl）中毒大鼠体内的药代动力学特征。还利用晚期肝细胞癌患者的微粒体研究了这四种木脂素的代谢情况。进行了肠道和肝脏灌注实验，以阐明肠道和肝脏功能受损对CCl中毒大鼠体内四种五味子木脂素药代动力学的影响。研究了大鼠和人肝微粒体中的代谢以及Caco-2单层细胞模型中的转运，以揭示这四种木脂素处置的关键因素。当将五味子醇提取物短期（4天）口服给予CCl中毒大鼠时，四种活性五味子木脂素的药代动力学发生了显著变化，而其肝治疗效果未明显观察到。与对照组相比，四种五味子木脂素的血浆浓度显著升高。在CCl预处理的大鼠中，Cmax、AUC和MRT均显著增加或延长，而参数CLz/F明显降低。在肝脏灌注研究和肝微粒体孵育中发现，这四种木脂素的肝脏代谢明显降低，主要是由于参与代谢的多种CYP450同工酶活性降低，最终可能导致它们在CCl中毒大鼠或晚期肝细胞癌患者体内药代动力学特征的改变。肝功能不全病理状态下五味子成分的药代动力学研究有望为五味子制剂在临床的合理安全应用或进一步的药理毒理学研究提供有用的数据。
