Effects of red ginseng extract on the pharmacokinetics and disposition of warfarin via intestinal Cyp2c11 modulation in rats

초록

PurposeThis study aimed to develop and validate the analytical method for warfarin and its major metabolite 7-hydroxy warfarin using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) as well as to conduct pharmacokinetic and elimination studies on warfarin in rats.MethodsThe LC-MS/MS analytical method for warfarin and 7-hydroxy warfarin was used and validated. Mice were administered warfarin (1 mg/kg) with or without the coadministration of Korean red ginseng extract (RGE, 2 g/kg/day) once or multiple times for 7 days. Thereafter, the pharmacokinetics and disposition of warfarin and 7-hydroxy warfarin were measured. The underlying mechanisms of their pharmacokinetic alterations were observed by measuring Cyp2c11 expression in the intestine and liver and by investigating the inhibitory effects of RGE and ginsenoside Rb1 on warfarin metabolism in rat intestinal and liver microsomes.ResultsWe demonstrated good linearity in a range of 20-15,000 ng/mL for warfarin and 1-500 ng/mL for 7-hydroxy warfarin by using liquid-liquid extraction with ethyl acetate. The analytical method for this study is more reliable for conducting pharmacokinetic and elimination studies with acceptable accuracy, precision, recovery, and matrix effect. During the RGE treatment, warfarin concentration increased and the metabolic activity from warfarin to 7-hydroxy warfarin decreased in rats. Moreover, RGE treatment decreased the protein expression of Cyp2c11, the responsible metabolizing enzyme of warfarin, in rat intestine but not the liver. Ginsenoside Rb1, the most abundant ginsenoside in RGE, also inhibited the metabolic activity of Cyp2c11 in the intestine but not in the liver.ConclusionThe herb-drug interactions between RGE and warfarin occurred via intestinal Cyp2c11 inhibition (for single administration of RGE) as well as decreased intestinal Cyp2c11 expression (for repeated administration of RGE) in rats.

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