Journal
JOURNAL OF PHARMACY AND PHARMACOLOGY
Volume 72, Issue 7, Pages 979-989Publisher
OXFORD UNIV PRESS
DOI: 10.1111/jphp.13268
Keywords
apatinib; cytochrome P450 enzymes; Huosu Yangwei oral liquid; pharmacokinetic interaction
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Funding
- National Key Research and Development Program of China [2017YFC1700200, 2017YFC1702000]
- NSF of China [81922070, 81703604, 81973286, 81773687, 81573501]
- Program of Shanghai Academic/Technology Research Leader [18XD1403600]
- Cultivation Project of Clinical Research of Shanghai Shenkang Hospital Development Center
- Three-year Action Plan of Shanghai TCM Development [ZY-(2018-2020)-CCCX-5001]
- Shanghai Education Development Foundation [18SG40]
- Shanghai Municipal Education Commission
- Program for Innovative Leading Talents of Qinghai Province (2018)
- Program for Innovative Leading Talents of Qinghai Province (2019)
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Objectives This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. Methods Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. Key findings Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC(0-inf) (nm center dot h) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. Conclusions Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.
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