In Vitro and In Vivo Evaluation of Puerarin on Hepatic Cytochrome P450-Mediated Drug Metabolism
간 사이트크롬 P450 약물 대사에서 Puerarin이 미치는 영향에 대한 연구
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2014. 8. 김대덕.
- Puerarin (PU, 8-β-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a major pharmacological component of Puerariae Radix, the root of Pueraria lobata (Willd) Ohwi. The effect of PU on hepatic cytochrome P450 (CYP)-mediated drug metabolism in rats and human was investigated. The in vitro CYP inhibitory effect of PU in human and rat liver microsomes (HLM and RLM, respectively) was evaluated using the following model CYP substrates
i.e., phenacetin (PHE) for CYP1A, diclofenac (DIC) for CYP2C, dextromethorphan (DEX) for CYP2D, and testosterone (TES) for CYP3A. The in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with single simultaneous intravenous co-administration of PU in rats. In the in vitro CYP inhibition study, the rate of disappearance of TES was significantly reduced in the presence of 10-μM PU, while that of other CYP substrates was not significantly affected in both HLM and RLM, suggesting that PU inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and rat systems (IC50 = 15.5 ± 3.9 μM). After intravenous administration of BUS with single simultaneous co-administration of intravenous PU at a dose of 10 mg/kg in rats, the AUC was increased while CL decreased. When BUS was orally administered in rats with the 10 mg/kg intravenous PU co-administration, both AUC and F were significantly increased. Therefore, results of the in vitro microsomal and in vivo pharmacokinetic studies suggest the possible inhibition of hepatic CYP3A-mediated drug metabolism by PU administration, potentially leading to metabolism-mediated herb–drug interactions with clinical significance.