in vitro metabolism of daphnetin in rat liver S9 fractions
10.16438/j.0513-4870.2016-0847
- VernacularTitle:瑞香素在大鼠肝S9中体外代谢研究
- Author:
Si-cheng LIANG
1
;
Guang-bo GE
1
;
Yang-liu XIA
1
;
Xiao-yi QI
2
;
Ao-xue WANG
2
;
Cai-xia TU
2
;
Ling YANG
1
Author Information
1. Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
2. University of Chinese Academy of Sciences, Beijing 100049, China
- Publication Type:ORIGINAL ARTICLES
- Keywords:
daphnetin;
phase II enzyme;
enzyme kinetics;
hepatic clearance
- From:
Acta Pharmaceutica Sinica
2017;52(2):291-295
- CountryChina
- Language:Chinese
-
Abstract:
Daphnetin is quickly eliminated in rats after dosing, but the mechanism remains unclear. This study was aimed to investigate the in vitro metabolism of daphnetin using rat liver S9 fractions (RLS9). The metabolites formed in RLS9 were identified and the kinetic parameters for different metabolic pathways were determined. HPLC-DAD-MS analysis showed that daphnetin was biotransformed to six metabolites, which were identified as 7 or 8 mono-glucuronide and mono-sulfate, 8-methylate, and 7-suflo-8-methylate. Methylation and glucuronidation of daphnetin exhibited the Michaelis-Menten kinetic characteristics, whereas the substrate inhibition kinetic and the two-site kinetic were observed for 8-sulfate and 7-sulfate formations. Of the 3 conjugation pathways, the intrinsic clearance rate for sulfation was highest, followed by methylation and glucuronidation. By in vitro-in vivo extrapolation of the kinetic data measured in RLS9, the hepatic clearance were estimated to be 54.9 mL·min-1·kg-1 which is comparable to the system clearance (58.5 mL·min-1·kg-1) observed in rats. In conclusions, the liver might be the main site for daphnetin metabolism in rats. Sulfation, methylation and glucuronidation are important pathways of the hepatic metabolism of daphnetin in rats.
