以安全性为导向的香加皮强心苷类成分药代动力学研究

Cortex periplocae, belonging to Toxic Chinese Materia Medica, was constituted effective Chinese patent medicines to treat heart failure and used more and more widely. Cardiotonic glycoside compounds originated from cortex periplocae are both active and toxic constituents. The cardiac glycoside compounds play unique role of cardiotonic effect without increasing cardiac oxygen consumption for patients with heart failure at low concentration in blood. However, the cardiac glycoside compounds have a narrow therapeutic range and may lead to lethal cardiotoxicity after drug overdose. Due to lack of pharmacokinetics study, it is unclear about the relationship between dosage of cardiotonic glycoside compounds of cortex periplocae and their in vivo exposure. Additionally, there is little known about the disposition mechanism of the cardiac glycoside compounds in absorption, metabolism and excretion process. Hence that there is potential toxic risk due to exposure increasing after any link of disposition of cardiotonic glycoside compounds was interrupted. Focusing on the cardiac glycoside compounds having systemic exposure levels after administration of cortex periplocae extract at toxic dosage, the relationship between dosage and in vivo exposure and pharmacokinetics characteristics at toxic dose of cardiotonic glycoside compounds of cortex periplocae will be studied. In addition, methods based on molecular or cellular level including artificial gastric juice with different pH, in vitro intestinal bacteria anaerobic incubation, cDNA expressed human P450s enzyme, Hek293 transient transfection assay, et al. will be used to investigate the absorption, metabolism, and excretion about mechanism of the cardiac glycoside compounds. Finally, the toxic risk will be assessed due to exposure increasing of the cardiac glycosides caused by concomitant medication of cortex periplocae and other drugs in clinic. The current study will provide evidences for quality control of cortex periplocae and Chinese patent medicines containing cortex periplocae and clinical rational use of Chinese patent medicines containing cortex periplocae with other drugs to avoid the absorption-, metabolism- or transporter-mediated safety issues.

有毒中药香加皮及含香加皮中成药治疗心衰的应用日益广泛，其强心苷类成分对衰竭心脏具有强心且不增加耗氧量的独到作用，低浓度即发挥药效，但治疗窗窄，过量可导致严重的心脏毒性。因为香加皮强心苷类成分药动学研究少，对其剂量与暴露的关系及影响其体内处置过程导致暴露增强而致心脏中毒的风险尚不清楚，造成临床应用的安全隐患。本研究拟以香加皮心脏中毒剂量给药后体内有暴露的强心苷成分为研究对象，考察香加皮强心苷类成分剂量与暴露的关系，采用人工胃液、离体肠道菌厌氧孵育、人重组P450酶和Hek293细胞瞬时转染等技术，从分子或细胞水平研究胃pH值、肠道菌、代谢酶及转运体对强心苷成分的吸收、代谢、排泄机制并比较种属差异，并从整体动物水平评价联合用药可能影响香加皮强心苷类成分体内暴露而致心脏毒性的风险。本研究将为香加皮及含香加皮中成药质量控制的完善提供有价值的基础数据，为含香加皮中成药临床安全用药提供科学指导。

有毒中药香加皮及含香加皮中成药治疗心衰的应用日益广泛，但对其强心苷类成分药动学研究少，对其剂量与暴露的关系及影响其体内处置过程导致暴露增强而致心脏中毒的风险尚不清楚，造成临床应用的安全隐患。.香加皮中发现41种化学成分，杠柳毒苷含量最高，但其大鼠体内暴露很低，杠柳次苷和杠柳苷M在体内暴露量相对较高。单体静注后，杠柳苷元和杠柳苷N从大鼠体内迅速消除，杠柳苷M和N的暴露存在明显的性别差异。杠柳次苷，杠柳苷元、杠柳苷M和杠柳苷N的表观分布容积（Vd）均在0.5~3 L/kg之间，低于杠柳毒苷的Vd。大鼠灌胃给予不同剂量的香加皮提取物后，杠柳毒苷在大鼠体内的暴露和生物利用度（F）极低。灌胃给药后，杠柳次苷、杠柳苷元、杠柳苷M和N的半衰期（t1/2）均显著延长，F均大于100%。除杠柳毒苷外，其他四种甾体的暴露与剂量呈正相关但均非线性相关。杠柳毒苷、杠柳苷M和N多次给药后产生蓄积，杠柳次苷和杠柳苷元连续给药后的暴露明显降低。5种化合物在大部分组织中均有分布，五种甾体类成分均可透过血脑屏障。杠柳毒苷、杠柳次苷、杠柳苷元和杠柳苷M经尿液和粪便的总累积排泄率均小于15%；杠柳苷N经尿液和粪便的总累积排泄率约为70%。杠柳毒苷和杠柳次苷在胃液中转化成杠柳苷元，香加皮提取物种未知化合物在胃液种转化成杠柳苷元、杠柳苷M和N。五种甾体类化合物均在大鼠肠道菌的作用下发生降解，而在人肠道菌群只能降解杠柳毒苷和杠柳苷M。肝微粒体不代谢杠柳毒苷；杠柳次苷和杠柳苷元在肝微粒体中发生I相代谢反应，且存在种属差异。干扰胃酸分泌可影响杠柳毒苷和杠柳次苷体内的暴露，抑制肠道菌则可以影响杠柳毒苷、杠柳次苷和杠柳苷元的体内暴露。.本研究将为香加皮及含香加皮中成药质量控制的完善提供有价值的基础数据，为按现代药物标准开展香加皮的安全性研究指明应关注的中药物质，为含香加皮中成药临床安全用药提供科学指导。