[In vitro metabolism of daphnetin in rat liver S9 fractions].

药学学报 Pub Date : 2017-02-01

Si-cheng Liang, Guang-bo Ge, Yang-liu Xia, Xiao-yi Qi, Ao-xue Wang, Cai-xia Tu, Ling Yang

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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.

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[大鼠肝脏S9组分中瑞香素的体外代谢研究]。

给药后，瑞香素在大鼠体内迅速消失，但其机制尚不清楚。本研究旨在探讨大鼠肝脏S9组分(RLS9)对瑞香素体外代谢的影响。鉴定了RLS9中形成的代谢产物，并测定了不同代谢途径的动力学参数。HPLC-DAD-MS分析表明，瑞香素被生物转化为6种代谢物，分别为7、8单葡糖苷和单硫酸酯、8-甲基化酯和7-氟-8-甲基化酯。瑞香素的甲基化和葡萄糖醛酸化反应表现出Michaelis-Menten动力学特征，而8-硫酸盐和7-硫酸盐反应则表现出底物抑制动力学和两位点动力学。在3种偶联途径中，硫酸化的内在清除率最高，其次是甲基化和葡萄糖醛酸化。通过对RLS9中测量的动力学数据进行体内外推，肝脏清除率估计为54.9 mL·min - 1·kg - 1，与大鼠观察到的系统清除率(58.5 mL·min - 1·kg - 1)相当。由此可见，肝脏可能是大鼠体内瑞香素代谢的主要部位。巯基化、甲基化和葡萄糖醛酸化是大鼠肝代谢的重要途径。

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来源期刊

药学学报 Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

1.20

自引率

0.00%

发文量

期刊介绍： Acta Pharmaceutica Sinica B (APSB) is a bimonthly English peer-reviewed online journal in ScienceDirect, which publishes significant original research articles, communications and high quality reviews of recent advances. APSB encourages submissions from all areas of pharmaceutical sciences, including pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis and pharmacokinetics. APSB is a part of the series Acta Pharmaceutica Sinica, which was founded in 1953. The journal is co-published by Elsevier B.V., in association with the Institute of MateriaMedica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.