State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2019 Oct;40(10):1351-1363. doi: 10.1038/s41401-019-0273-1. Epub 2019 Jul 29.
XueShuanTong, a lyophilized extract of Panax notoginseng roots (Sanqi) for intravenous administration, is extensively used as add-on therapy in the treatment of ischemic heart and cerebrovascular diseases and comprises therapeutically active ginsenosides. Potential for XueShuanTong-drug interactions was determined; the investigation focused on cytochrome P450 (CYP)3A induction and organic anion-transporting polypeptide (OATP)1B inhibition. Ginsenosides considerably bioavailable for drug interactions were identified by dosing XueShuanTong in human subjects and their interaction-related pharmacokinetics were determined. The CYP3A induction potential was determined by repeatedly dosing XueShuanTong for 15 days in human subjects and by treating cryopreserved human hepatocytes with circulating ginsenosides; midazolam served as a probe substrate. Joint inhibition of OATP1B by XueShuanTong ginsenosides was assessed in vitro, and the data were processed using the Chou-Talalay method. Samples were analyzed by liquid chromatography/mass spectrometry. Ginsenosides Rb, Rd, and Rg and notoginsenoside R were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb and Rd, long terminal half-lives (32‒57 and 58‒307 h, respectively) and low unbound fractions in plasma (0.8%‒2.9% and 0.4%‒3.0%, respectively). Dosing XueShuanTong did not induce CYP3A. Based on the pharmacokinetics and inhibitory potency of the ginsenosides, XueShuanTong was predicted to have high potential for OATP1B3-mediated drug interactions (attributed chiefly to ginsenoside Rb) suggesting the need for further model-based determination of the interaction potential for XueShuanTong and, if necessary, a clinical drug interaction study. Increased awareness of ginsenosides' pharmacokinetics and XueShuanTong-drug interaction potential will help ensure the safe use of XueShuanTong and coadministered synthetic drugs.
血塞通，一种从三七（人参）根提取的冻干提取物，用于静脉注射，广泛用于治疗缺血性心脏病和脑血管疾病的辅助治疗，包含治疗活性的人参皂苷。研究人员确定了血塞通的药物相互作用潜力；研究重点是细胞色素 P450（CYP）3A 诱导和有机阴离子转运多肽（OATP）1B 抑制。通过给人体服用血塞通来确定可用于药物相互作用的大量生物利用的人参皂苷，并确定其相互作用相关的药代动力学。通过在人体中重复服用血塞通 15 天和用循环人参皂苷处理冷冻保存的人肝细胞来确定 CYP3A 诱导潜力；咪达唑仑作为探针底物。在体外评估了血塞通人参皂苷对 OATP1B 的联合抑制作用，并使用 Chou-Talalay 方法处理数据。通过液相色谱/质谱分析样品。人参皂苷 Rb、Rd 和 Rg 和三七皂苷 R 是主要的循环血塞通化合物；其相互作用相关的药代动力学包括化合物剂量依赖性的全身暴露水平，以及人参皂苷 Rb 和 Rd 的长终末半衰期（分别为 32-57 和 58-307 小时）和低血浆未结合分数（分别为 0.8%-2.9%和 0.4%-3.0%）。给人体服用血塞通不会诱导 CYP3A。基于人参皂苷的药代动力学和抑制效力，预测血塞通具有高的 OATP1B3 介导的药物相互作用潜力（主要归因于人参皂苷 Rb），这表明需要进一步基于模型确定血塞通的相互作用潜力，如果必要，还需要进行临床药物相互作用研究。提高对人参皂苷药代动力学和血塞通药物相互作用潜力的认识，将有助于确保血塞通和同时使用的合成药物的安全使用。
