In vitro metabolism of mifepristone (RU-486) in rat, monkey and human hepatic S9 fractions: identification of three new mifepristone metabolites.
1. In vitro metabolism of the antiprogestin drug mifepristone (RU-486) was studied after incubation with rat, monkey and human hepatic S9 fractions in the presence of an NADPH-generating system. 2. Unchanged mifepristone (approximately 45% of the sample(s) in rat; approximately 70% in monkey; approximately 65% in human) plus six metabolites, three known and three new, were profiled, quantified and tentatively identified on the basis of MS and MS/MS data. 3. The proposed metabolic pathways for mifepristone are proposed, and the two metabolic steps are (A) N-demethylation and (B) methyl oxidation. 4. Step A formed N-desmethyl mifepristone (M1) in major amounts (approximately 35% s in rat, 16% in monkey and human) and N,N-didesmethyl mifepristone (M2) in minor amounts (< 5% s in all species). Step B, or in conjunction with step A, produced four minor/trace metabolites, namely hydroxymethyl mifepristone (M3), hydroxymethyl M1 (M4), hydroxymethyl M2 (M5) and formyl mifepristone (M6).
Wu
W N
WN
Department of Drug Metabolism, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
McKown
L A
LA
Moyer
M D
MD
Johannsen
T B
TB
Takacs
A R
AR
D000085:Acetates / Q000737:chemistry; D000818:Animals; D001711:Biotransformation; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D015735:Mifepristone / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism*
D000085:Acetates; D015735:Mifepristone