Effects of Silymarin, Glycyrrhizin, and Oxymatrine on the Pharmacokinetics of Ribavirin and Its Major Metabolite in Rats

The herb-derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (PO) administration of ribavirin (30mg/kg) with or without silymarin (40mg/kg, PO), glycyrrhizin (15mg/kg, intraperitoneal [IP]), or oxymatrine (60mg/kg, PO). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration-time curve (AUC(0-t)) and the peak plasma concentration (C-max) of ribavirin and ribavirin base by 31.2-44.5% and 48.9-50.0%, respectively. Glycyrrhizin significantly decreased the C-max and AUC(0-t) of both ribavirin and its metabolite by 35.3-37.6% and 38.6-39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and C-max. Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the C-max (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine. Copyright (c) 2016 John Wiley & Sons, Ltd.