Abstract
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 Rb1, Rd, and Rg1 and notoginsenoside R1 were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb1 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.
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Acknowledgements
This work was supported in part by the National Key R&D Program of China (Grant 2018YFC1704500); by the National Science and Technology Major Project of China “Key New Drug Creation and Manufacturing Program” (Grants 2012ZX09101201-005 and 2017ZX09301012-006); by the National Natural Science Foundation of China (Grant 81673582); by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDA12050306); and by the National Basic Research Program of China (Grant 2012CB518403).
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Participated in the research design: CL, JLY, WN, YHH, SP. Conducted experiments: JLY, SP, WN, XND, OEO, FQW, YFL. Performed the data analysis: CL, JLY, SP, WN. Wrote or contributed to the writing of the manuscript: CL, SP, JLY.
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Pintusophon, S., Niu, W., Duan, Xn. et al. Intravenous formulation of Panax notoginseng root extract: human pharmacokinetics of ginsenosides and potential for perpetrating drug interactions. Acta Pharmacol Sin 40, 1351–1363 (2019). https://doi.org/10.1038/s41401-019-0273-1
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DOI: https://doi.org/10.1038/s41401-019-0273-1
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