Metabolism of megestrol acetate in vitro and the role of oxidative metabolites.

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House L, Seminerio MJ, Mirkov S, Ramirez J, Skor M, Sachleben JR, Isikbay M, Singhal H, Greene GL, Vander Griend D, Conzen SD, Ratain MJ

Metabolism of megestrol acetate in vitro and the role of oxidative metabolites.

Xenobiotica. 2018 Oct;48(10):973-983. doi: 10.1080/00498254.2017.1386335. Epub 2017 Nov 10.

PubMed ID
29050522 [ View in PubMed
]
Abstract

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 muM (HLM Km for metabolite 1; M1) and 28 muM (HLM Km for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 muM MA. 3. At 28 muM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
Megestrol acetateCytochrome P450 3A4ProteinHumans
No
Substrate
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