Intravenous formulation of Panax notoginseng root extract: human pharmacokinetics of ginsenosides and potential for perpetrating drug interactions
Intravenous formulation of Panax notoginseng root extract: human pharmacokinetics of ginsenosides and potential for perpetrating drug interactions
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DOI：
10.1038/s41401-019-0273-1
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发表时间：
2019-10-01
影响因子：
8.2
通讯作者：
Li, Chuan
中科院分区：
文献类型：
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作者：
Pintusophon, Salisa;Niu, Wei;Li, Chuan
血栓通是一种用于静脉给药的三七根（三七）的冻干提取物，被广泛用作治疗缺血性心脏和脑血管疾病的附加疗法，并且包含治疗活性三七皂苷。确定了血栓通-药物相互作用的可能性;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。通过人体给药血栓通，确定了具有相当生物利用度的人参皂苷，并测定了其相互作用相关的药代动力学。CYP 3A诱导潜力通过在人类受试者中重复给药血栓通15天以及通过用循环的甘草苷处理冻存的人肝细胞来确定;咪达唑仑作为探针底物。在体外评估血栓通人参皂苷对OATP 1B的联合抑制作用，并使用Chou-Talalay方法处理数据。通过液相色谱/质谱法分析样品。血栓通主要循环成分为人参皂苷Rb-1、Rd、Rg（1）和三七皂苷R-1;它们的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，对于皂苷Rb-1和Rd，终末半衰期较长（分别为32-57和58-307 h）和血浆中的低未结合分数（分别为0.8%-2.9%和0.4%-3.0%）。血栓通对CYP 3A无诱导作用。基于黄芩苷的药代动力学和抑制效力，预测血栓通具有较高的OATP 1B 3介导的药物相互作用潜力（主要归因于OATP Rb 1），这表明需要进一步基于模型确定血栓通的相互作用潜力，如有必要，还需要进行临床药物相互作用研究。提高对黄芪皂苷药代动力学和血栓通-药物相互作用潜力的认识将有助于确保血栓通和联合给药的合成药物的安全使用。
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-1, Rd, and Rg(1) and notoginsenoside R-1 were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb-1 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 Rb1) 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.