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题名: Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate
作者: Zhang, Jiang-Wei1, 2;  Liu, Yong1;  Zhao, Jiu-Yang3;  Wang, Li-Ming3;  Ge, Guang-Bo1, 2;  Gao, Yang3;  Li, Wei1, 2;  Liu, Hong-Tao1, 2;  Liu, Hui-Xin1, 2;  Zhang, Yan-Yan1, 2;  Sun, Jie3;  Yang, Ling1
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2008-11-01
DOI: 10.1124/dmd.108.022525
卷: 36, 期:11, 页:2292-2298
收录类别: SCI
文章类型: Article
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: Medroxyprogesterone acetate (MPA) is one of the most frequently prescribed progestins for conception, hormone replacement therapy, and adjuvant endocrine therapy. MPA has a low oral bioavailability because of extensive metabolism; however, its metabolism was poorly documented. This study was intended to profile the phase I metabolites of MPA and the cytochrome P450 ( P450) isoforms involved. After MPA was incubated with human liver microsomes and the NADPH-generating system, five main metabolites (namely M-1, M-2, M-3, M-4, and M-5) were isolated by high-performance liquid chromatography. Three major metabolites (M-2, M-4, and M-3) were tentatively identified to be 6 beta-, 2 beta-, and 1 beta-hydroxy MPA by liquid chromatography/mass spectrometry and (1)H nuclear magnetic resonance. By consecutive metabolism of purified M-2, M-3, and M-4, M-1 and M-5 were proposed to be 2 beta-, 6 beta-dihydroxy MPA, and 1,2-dehydro MPA, respectively. CYP3A4 was identified to be the isoform primarily involved in the formation of M-2, M-3, and M-4 in studies with specific P450 inhibitors, recombinant P450s, and correlation analysis. Rat and minipig liver microsomes were included evaluating species differences, and the results showed little difference among the species. In human liver microsomes, the K(m) values ranged from 10.0 to 11.2 mu M, and the V(m) values ranged from 194 to 437 pmol/min/mg for M-2, M-3, and M-4. In conclusion, CYP3A4 was the major P450 isoform involved in MPA hydroxylation, with 6 beta, 2 beta, and 1 beta being the possible hydroxylation sites. Minipig and rat could be the surrogate models for man in MPA pharmacokinetic studies.
关键词[WOS]: HEALTHY POSTMENOPAUSAL WOMEN ;  ESTROGEN PLUS PROGESTIN ;  BREAST-CANCER ;  LIVER-MICROSOMES ;  IN-VITRO ;  ISOFORMS ;  INHIBITORS ;  MECHANISM ;  THERAPY ;  ENZYMES
语种: 英语
WOS记录号: WOS:000260132100018
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141129
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
3.Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China

Recommended Citation:
Zhang, Jiang-Wei,Liu, Yong,Zhao, Jiu-Yang,et al. Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate[J]. DRUG METABOLISM AND DISPOSITION,2008,36(11):2292-2298.
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