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

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Received for publication June 23, 2008.
Revised August 19, 2008.
Accepted for publication August 20, 2008.

Metabolic profiling and P450 reaction phenotyping of medroxyprogesterone acetate

Jiang-Wei Zhang 1, Yong Liu 1, Jiu-Yang Zhao 2, Li-Ming Wang 2, Guang-Bo Ge 1, Yang Gao 2, Wei Li 3, Hong-Tao Liu 3, Hui-Xin Liu 3, Yan-Yan Zhang 3, Jie Sun 2, Ling Yang 3*

1 Dalian Institute of Chemical Physics,Chinese Academy of Sciences 2 The Second Affiliated Hospital of Dalian Medical University 3 Dalian Institute of Chemical Physics, Chinese Academy of Sciences

* Address correspondence to: E-mail: yling{at}dicp.ac.cn

Abstract

Medroxyprogesterone acetate (MPA) is one of the most frequently prescribed progestin for conception, hormone replacement therapy, and adjuvant endocrine therapy. MPA has a low oral bioavailability due to extensive metabolism; however, its metabolism was poorly documented. This study was intended to profile the phase I metabolites of MPA and the P450 isoforms involved. After MPA was incubated with human liver microsomes and NADPH-generating system, five main metabolites (namely M-1, M-2, M-3, M-4, and M-5) were isolated by HPLC. 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 LC/MS and 1HNMR. 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 Km values ranged from 10.0 to 11.2 µM, 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 CYP 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.


Key words: CYP3A, cytochrome P450 catalyzed oxidations, liver microsomes, metabolite identification, steroids




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