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

• Published in: Acta pharmacologica Sinica Vol. 40; no. 10; pp. 1351 - 1363
• Main Authors: Pintusophon, Salisa, Niu, Wei, Duan, Xiao-na, Olaleye, Olajide E, Huang, Yu-hong, Wang, Feng-qing, Li, Yan-fen, Yang, Jun-ling, Li, Chuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2019; Nature Publishing Group
• Subjects: Administration, Intravenous; Adult; Biomedical and Life Sciences; Biomedicine; Cerebrovascular diseases; Chromatography, Liquid; Coronary artery disease; Cryopreservation; Cytochrome P-450 CYP3A - biosynthesis; Cytochrome P450; Dosage; Drug Compounding; Drug dosages; Drug interaction; Drug Interactions; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacokinetics; Female; Ginsenosides; Ginsenosides - administration & dosage; Ginsenosides - chemistry; Ginsenosides - pharmacokinetics; Healthy Volunteers; Heart diseases; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Human subjects; Humans; Immunology; Internal Medicine; Intravenous administration; Ischemia; Liquid chromatography; Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors; Liver-Specific Organic Anion Transporter 1 - metabolism; Male; Mass Spectrometry; Mass spectroscopy; Medical Microbiology; Midazolam; Molecular Conformation; Organic anion transporting polypeptide; Panax notoginseng; Pharmacokinetics; Pharmacology/Toxicology; Plant Roots - chemistry; Vaccine; Vascular diseases; Young Adult; ginsenoside; herbal medicine–drug interactions; organic anion-transporting polypeptide 1B3; cytochrome P450 3A; XueShuanTong; Panax notoginseng
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-019-0273-1

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 Rb 1 ) 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.