TY - JOUR
T1 - Metabolism of megestrol acetate in vitro and the role of oxidative metabolites
AU - House, Larry
AU - Seminerio, Michael J.
AU - Mirkov, Snezana
AU - Ramirez, Jacqueline
AU - Skor, Maxwell
AU - Sachleben, Joseph R.
AU - Isikbay, Masis
AU - Singhal, Hari
AU - Greene, Geoffrey L.
AU - Vander Griend, Donald
AU - Conzen, Suzanne D.
AU - Ratain, Mark J.
N1 - Publisher Copyright:
© 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2018/10/3
Y1 - 2018/10/3
N2 - 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 μM (HLM Km for metabolite 1; M1) and 28 μM (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 μM MA. 3. At 28 μM 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.
AB - 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 μM (HLM Km for metabolite 1; M1) and 28 μM (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 μM MA. 3. At 28 μM 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.
KW - Androgen receptor
KW - drug interaction
KW - glucocorticoid receptor
KW - megestrol acetate
KW - metabolite activity
KW - metabolite structure
KW - progesterone receptor
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U2 - 10.1080/00498254.2017.1386335
DO - 10.1080/00498254.2017.1386335
M3 - Article
C2 - 29050522
AN - SCOPUS:85033685437
SN - 0049-8254
VL - 48
SP - 973
EP - 983
JO - Xenobiotica
JF - Xenobiotica
IS - 10
ER -