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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 저널정보
- 한국약제학회 Journal of Pharmaceutical Investigation Journal of Pharmaceutical Investigation Vol.54 No.1
- 발행연도
- 2024.1
- 수록면
- 85 - 97 (13page)
- DOI
- 10.1007/s40005-023-00650-x
이용수
초록· 키워드
오류제보하기
Purpose This 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.
Methods The 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.
Results We 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.
Conclusion The 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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