Impact of the herbal medicine Sophora flavescens on the oral pharmacokinetics of indinavir in rats: the involvement of CYP3A and P-glycoprotein

• Published in: PloS one 2012-02, Vol.7 (2), p.e31312
• Main Authors: Yang, Jia-Ming, Ip, Siu-Po, Xian, Yanfang, Zhao, Ming, Lin, Zhi-Xiu, Yeung, John Hok Keung, Chan, Raphael Chiu Yeung, Lee, Shui-Shan, Che, Chun-Tao
• Format: Article
• Language: English
• Subjects: Acetic acid; Acquired immune deficiency syndrome; Administration, Oral; AIDS; AIDS treatment; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Biology; Chemistry; Chinese medicine; Cytochrome; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - physiology; Data analysis; Descriptive labeling; Dosage and administration; Drug dosages; Enzymes; Esters; Ethyl acetate; Federal regulation; Gene expression; Glycoproteins; Hemorrhage; Hepatitis; Herb-Drug Interactions; Herbal medicine; Herbal Medicine - methods; Herbs; HIV; Human immunodeficiency virus; Indinavir; Indinavir - administration & dosage; Indinavir - blood; Indinavir - pharmacokinetics; Liver; Medical research; Medical treatment; Medicinal plants; Medicine; Metabolism; Natural products; Oral administration; P-Glycoprotein; Pharmaceutical industry; Pharmaceutical sciences; Pharmacokinetics; Pharmacology; Plant Preparations - blood; Plant Preparations - pharmacokinetics; Plasma; Proteases; Rats; RNA; RNA, Messenger - analysis; Rodents; Skin diseases; Small intestine; Sophora; Sophora flavescens; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031312

Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%-83% decrease in AUC(0-∞) and 38%-78% reduction in C(max). The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.