Investigation of the pharmacokinetics and metabolic fate of Fasiglifam (TAK-875) in male and female rats following oral and intravenous administration

Molloy, Billy J, King, Adam, Gethings, Lee A, Plumb, Robert S, Mortishire-Smith, Russell J and Wilson, Ian D ORCID: 0000-0002-8558-7394 (2023) Investigation of the pharmacokinetics and metabolic fate of Fasiglifam (TAK-875) in male and female rats following oral and intravenous administration. XENOBIOTICA, 53 (2). pp. 93-105.

Access the full-text of this item by clicking on the Open Access link.

Abstract

The metabolism and pharmacokinetics of fasiglifam (TAK-875, 2-[(3<i>S</i>)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid), a selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist, were studied following intravenous (5 mg/kg) and oral administration (10 and 50 mg/kg) to male and female Sprague Dawley rats.Following intravenous dosing at 5 mg/kg, peak observed plasma concentrations of 8.8/9.2 µg/ml were seen in male and female rats respectively.Following oral dosing, peak plasma concentrations at 1 h of ca. 12.4/12.9 µg/ml for 10 mg/kg and 76.2/83.7 µg/ml for 50 mg/kg doses were obtained for male and female rats respectively. Drug concentrations then declined in the plasma of both sexes with t_1/2's of 12.4 (male) and 11.2 h (female). Oral bioavailability was estimated to be 85-120% in males and females at both dose levels.Urinary excretion was low, but in a significant sex-related difference, female rats eliminated ca. 10-fold more drug-related material by this route.Fasiglifam was the principal drug-related compound in plasma, with 15 metabolites, including the acyl glucuronide, also detected. In addition to previously identified metabolites, a novel biotransformation, that produced a side-chain shortened metabolite via elimination of CH₂ from the acetyl side chain was noted with implications for drug toxicity.

Item Type:	Article
Uncontrolled Keywords:	Fasiglifam, pharmacokinetics, metabolite profiling, novel metabolites, oxidative decarboxylaton, sex differences
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	17 Apr 2023 09:46
Last Modified:	02 Aug 2023 15:30
DOI:	10.1080/00498254.2023.2179952
Open Access URL:	https://doi.org/10.1080/00498254.2023.2179952
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169607