Intravenous formulation of Panax notoginseng root extract: human pharmacokinetics of ginsenosides and potential for perpetrating drug interactions.

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.

• Authors: Salisa Pintusophon, Wei Niu, Xiao-Na Duan, Olajide E Olaleye, Yu-Hong Huang, Feng-Qing Wang, Yan-Fen Li, Jun-Ling Yang, Chuan Li
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 40 Issue 10 Pg. 1351-1363 (Oct 2019) ISSN: 1745-7254 [Electronic] United States
• PMID: 31358899 (Publication Type: Journal Article)

Chemical References

• Drugs, Chinese Herbal
• Ginsenosides
• Liver-Specific Organic Anion Transporter 1
• Panax notoginseng extract
• SLCO1B1 protein, human
• CYP3A protein, human
• Cytochrome P-450 CYP3A

Topics

• Administration, Intravenous
• Adult
• Chromatography, Liquid
• Cytochrome P-450 CYP3A (biosynthesis)
• Drug Compounding
• Drug Interactions
• Drugs, Chinese Herbal (administration & dosage, chemistry, pharmacokinetics)
• Female
• Ginsenosides (administration & dosage, chemistry, pharmacokinetics)
• Healthy Volunteers
• Hepatocytes (drug effects, metabolism)
• Humans
• Liver-Specific Organic Anion Transporter 1 (antagonists & inhibitors, metabolism)
• Male
• Mass Spectrometry
• Molecular Conformation
• Plant Roots (chemistry)
• Young Adult