Open AccessMetabolism and disposition of MM ‐433593, a selective FAAH ‐1 inhibitor, in monkeys
Author(s) -
Banijamali Ali R.,
Wakefield James D.,
Mermerian Ara H.,
Busby Robert W.
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.59
Subject(s) - metabolite , chemistry , in vivo , metabolism , pharmacokinetics , glucuronide , bioavailability , pharmacology , oral administration , glucuronic acid , glutathione , drug metabolism , glucuronidation , toxicokinetics , urine , in vitro , biochemistry , enzyme , biology , microsome , polysaccharide , microbiology and biotechnology
Abstract MM‐433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase‐1 (FAAH‐1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM‐433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM‐433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8–11 mL/min/kg. Absolute oral bioavailability was determined to be 14–21% with maximum plasma concentrations reached ~3 h ( T max ) following a 10 mg/kg oral dose. The average terminal half‐life of MM‐433593 was 17–20 h, and there were no qualitative sex differences in the metabolite profile of MM‐433593. The major site of metabolism was oxidation of the methyl group at the five position of the indole ring, which was confirmed by chromatography and mass spectrometry comparison to a synthesized authentic standard. This metabolite was further oxidized to the corresponding carboxylic acid and/or conjugated with sulfate, glucuronide, or glutathione. In all, 18 metabolites were found in plasma and urine. In vitro incubations of MM‐433593 with monkey hepatocytes yielded 13 metabolites, all of which were found in vivo, indicating a good correlation between the in vitro and in vivo metabolism data. A comprehensive pathway for the metabolism of MM‐433593 is proposed, including a plausible, five‐step biotransformation for the formation of N ‐acetylcysteine conjugate metabolite (M18) from the hydroxylated parent (M5).