title: Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys.
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).
authors.affiliation: Analytical Pharmacology/Drug Metabolism and Pharmacokinetics, Ironwood Pharmaceuticals Cambridge, Massachusetts.
authors.forename: Ali R
authors.initials: AR
authors.lastname: Banijamali
authors.affiliation: Analytical Pharmacology/Drug Metabolism and Pharmacokinetics, Ironwood Pharmaceuticals Cambridge, Massachusetts.
authors.forename: James D
authors.initials: JD
authors.lastname: Wakefield
authors.affiliation: Medicinal Chemistry, Ironwood Pharmaceuticals Cambridge, Massachusetts.
authors.forename: Ara H
authors.initials: AH
authors.lastname: Mermerian
authors.affiliation: Analytical Pharmacology/Drug Metabolism and Pharmacokinetics, Ironwood Pharmaceuticals Cambridge, Massachusetts.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Busby
keywords: Endocannabinoids; FAAH-1 inhibitor; N-acetylcysteine conjugate; glucuronide conjugate; hepatocyte metabolites; indole ketoamide; monkey pharmacokinetics; sulfate conjugate