DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on August 25, 2008; DOI: 10.1124/dmd.108.022525

0090-9556/08/3611-2292-2298$20.00
DMD 36:2292-2298, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.108.022525v1
36/11/2292    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, J.-W.
Right arrow Articles by Yang, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, J.-W.
Right arrow Articles by Yang, L.

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Jiang-Wei Zhang, Yong Liu, Jiu-Yang Zhao, Li-Ming Wang, Guang-Bo Ge, Yang Gao, Wei Li, Hong-Tao Liu, Hui-Xin Liu, Yan-Yan Zhang, Jie Sun, and Ling Yang

Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.-W.Z., Y.L., G.-B.G., W.L., H.-T.L., H.-X.L., Y.-Y.Z., L.Y.); Graduate School of Chinese Academy of Sciences, Beijing, China (J.-W.Z., G.-B.G., W.L., H.-T.L., H.-X.L., Y.-Y.Z.); and Second Affiliated Hospital of Dalian Medical University, Dalian, China (J.-Y.Z., L.-M.W., Y.G., J.S.)

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 6β-, 2β-, and 1β-hydroxy MPA by liquid chromatography/mass spectrometry and 1H nuclear magnetic resonance. By consecutive metabolism of purified M-2, M-3, and M-4, M-1 and M-5 were proposed to be 2β-, 6β-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 Km values ranged from 10.0 to 11.2 µM, and the Vm 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 6β, 2β, and 1β being the possible hydroxylation sites. Minipig and rat could be the surrogate models for man in MPA pharmacokinetic studies.

Address correspondence to: Dr. Ling Yang, Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. E-mail: yling{at}dicp.ac.cn






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.