Abstract
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 AUC0-∞ and 38%–78% reduction in Cmax. 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.
Highlights
Dried root of Sophora flavescens Ait. (Fabaceae), known in Chinese as Ku-Shen, is widely used in traditional Chinese Medicine as a ‘‘cooling’’ drug for the treatment of gastrointestinal hemorrhage, skin diseases, and pyretic stranguria
These findings suggest that there may be potential herb-drug interaction when S. flavescens is used, especially in conditions involving the prescription of multiple medicinal compounds, for example human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS)
The effect of Sophora extract on the multiple-dose pharmacokinetics of indinavir was assessed by measuring the plasma concentrations
Summary
Dried root of Sophora flavescens Ait. (Fabaceae), known in Chinese as Ku-Shen, is widely used in traditional Chinese Medicine as a ‘‘cooling’’ drug for the treatment of gastrointestinal hemorrhage, skin diseases, and pyretic stranguria. Phytochemical studies have revealed the presence of quinolizidine alkaloids and prenylated flavonoids [2,3], both of which show a wide spectrum of pharmacological activities, such as antitumor, cardioprotective, and neuroprotective effects [4,5,6] The alkaloids, such as matrine and oxymatrine, are frequently used as the chemical markers for the quality control of this medicinal herb. A mechanistic study using cellbased gene reporter assays demonstrated that S. flavescens induced CYP3A expression through the activation of pregnane X receptor (PXR), and N-methylcytisine, an alkaloid constituent of S. flavescens, was identified to be a potent PXR activator [10] Taken together, these findings suggest that there may be potential herb-drug interaction when S. flavescens is used, especially in conditions involving the prescription of multiple medicinal compounds, for example human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS)
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