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题名: Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes
作者: Zhang, Jiang-Wei;  Liu, Yong;  Li, Wei;  Hao, Da-Cheng;  Yang, Ling
通讯作者: 杨凌
关键词: cytochrome P450 ;  CYP2C9 ;  drug-drug interaction ;  medroxyprogesterone acetate (MPA) ;  phenytoin
刊名: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
发表日期: 2006-07-01
DOI: 10.1007/s00228-006-0128-9
卷: 62, 期:7, 页:497-502
收录类别: SCI
文章类型: Article
部门归属: 18
项目归属: 1806
产权排名: 1;1
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Objective: Medroxyprogesterone acetate (MPA), frequently used in contraception and chemotherapy, was involved in a report of drug-drug interaction (DDI) when co-administrated with phenytoin, doxifluridine and cyclophosphamide. In order to clarify the mechanism of such interaction, an in vitro study was undertaken to evaluate MPA's potential to inhibit cytochrome P450 (CYP) enzymes. Methods: Inhibitory effects of MPA on seven CYPs, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, were conducted in human liver microsomes. Time- and NADPH-dependent inhibitions were also tested. DDI potential was predicted according to the [I]/K-i value. Results: MPA was found to inhibit CYP2C9 and CYP3A4; half inhibition concentration (IC50) was 16.1 mu M and 31.5 mu M, respectively. Slight inhibition was observed on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 with IC50 of more than 100 mu M. MPA exhibited activation rather than inhibition on CYP2E1. Further study revealed that MPA showed a noncompetitive inhibition on CYP2C9 and a competitive inhibition on CYP3A4 with K (i) of 9.0 mu M and 36 mu M, respectively. In addition, MPA was not a mechanism-based inhibitor to any of seven isoforms tested. By using predicted concentration of MPA in liver, [I]/K (i) was estimated to be 0.24 and 0.06 for CYP2C9 and CYP3A4, respectively. The concentration of phenytoin co-administrated with MPA was calculated to increase by 24%. Conclusions: Based on our results, MPA can possibly cause clinically relevant DDI via the inhibition of CYP2C9.
关键词[WOS]: ADVANCED BREAST-CANCER ;  DRUG-DRUG INTERACTIONS ;  IN-VITRO ;  METABOLIC INTERACTION ;  ENDOGENOUS STEROIDS ;  5-FLUOROURACIL ;  MICROSOMES ;  3A4 ;  CYCLOPHOSPHAMIDE ;  DOXIFLURIDINE
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000238832200001
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/93865
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Sch, Beijing, Peoples R China

Recommended Citation:
Zhang, Jiang-Wei,Liu, Yong,Li, Wei,et al. Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes[J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY,2006,62(7):497-502.
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