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Banijamali AR, Wakefield JD, Mermerian AH, et al. Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys. Pharmacol Res Perspect. 2014;2(5):e00059doi: 10.1002/prp2.59.
Banijamali, A. R., Wakefield, J. D., Mermerian, A. H., & Busby, R. W. (2014). Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys. Pharmacology research & perspectives, 2(5), e00059. https://doi.org/10.1002/prp2.59
Banijamali, Ali R, et al. "Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys." Pharmacology research & perspectives vol. 2,5 (2014): e00059. doi: https://doi.org/10.1002/prp2.59
Banijamali AR, Wakefield JD, Mermerian AH, Busby RW. Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys. Pharmacol Res Perspect. 2014 Oct;2(5):e00059. doi: 10.1002/prp2.59. Epub 2014 Jul 02. PMID: 25505606; PMCID: PMC4186420.
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Pharmacol Res Perspect. 2014 Oct;2(5):e00059. doi: 10.1002/prp2.59. Epub 2014 Jul 02.

Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys.

Pharmacology research & perspectives

Ali R Banijamali, James D Wakefield, Ara H Mermerian, Robert W Busby

Affiliations

  1. Analytical Pharmacology/Drug Metabolism and Pharmacokinetics, Ironwood Pharmaceuticals Cambridge, Massachusetts.
  2. Medicinal Chemistry, Ironwood Pharmaceuticals Cambridge, Massachusetts.

PMID: 25505606 PMCID: PMC4186420 DOI: 10.1002/prp2.59

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).

Keywords: Endocannabinoids; FAAH-1 inhibitor; N-acetylcysteine conjugate; glucuronide conjugate; hepatocyte metabolites; indole ketoamide; monkey pharmacokinetics; sulfate conjugate

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