PT  - JOURNAL ARTICLE
AU  - Jiang-Wei Zhang
AU  - Yong Liu
AU  - Jiu-Yang Zhao
AU  - Li-Ming Wang
AU  - Guang-Bo Ge
AU  - Yang Gao
AU  - Wei Li
AU  - Hong-Tao Liu
AU  - Hui-Xin Liu
AU  - Yan-Yan Zhang
AU  - Jie Sun
AU  - Ling Yang
TI  - Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate
AID  - 10.1124/dmd.108.022525
DP  - 2008 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 2292--2298
VI  - 36
IP  - 11
4099  - http://dmd.aspetjournals.org/content/36/11/2292.short
4100  - http://dmd.aspetjournals.org/content/36/11/2292.full
SO  - Drug Metab Dispos2008 Nov 01; 36
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics