Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys
Article first published online: 2 JUL 2014
© 2014 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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Pharmacology Research & Perspectives
Volume 2, Issue 5, October 2014
How to Cite
Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys, Pharma Res Per, 2(5), 2014, e00059, doi: 10.1002/prp2.59, , , ,
- Issue published online: 2 JUL 2014
- Article first published online: 2 JUL 2014
- Manuscript Accepted: 27 MAY 2014
- Manuscript Received: 16 MAY 2014
- FAAH-1 inhibitor;
- glucuronide conjugate;
- hepatocyte metabolites;
- indole ketoamide;
- monkey pharmacokinetics;
- N-acetylcysteine conjugate;
- sulfate conjugate
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 (Tmax) 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).