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• W2008334346 abstract "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 6beta-, 2beta-, and 1beta-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 2beta-, 6beta-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 muM, 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 6beta, 2beta, and 1beta being the possible hydroxylation sites. Minipig and rat could be the surrogate models for man in MPA pharmacokinetic studies." @default.
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• W2008334346 date "2008-08-25" @default.
• W2008334346 modified "2023-10-11" @default.
• W2008334346 title "Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate" @default.
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• W2008334346 doi "https://doi.org/10.1124/dmd.108.022525" @default.
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