Investigation of the Pharmacokinetics and Metabolic Fate of Fasiglifam (TAK-875) in Male and Female Rats Following Oral and Intravenous Administration

by Selleckchem | Mar 27 2023

The metabolism and pharmacokinetics of fasiglifam (TAK-875, 2-[(3S)-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 t1/2'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.

Comments：

Fasiglifam (TAK-875) is a selective agonist of free fatty acid receptor 1 (FFAR1)/GPR40, which has potential as a treatment for type 2 diabetes. The pharmacokinetics and metabolism of fasiglifam were studied in male and female Sprague Dawley rats following intravenous and oral administration.

After intravenous dosing at 5 mg/kg, the peak observed plasma concentrations of fasiglifam were 8.8/9.2 μg/ml in male and female rats, respectively. Following oral dosing, peak plasma concentrations were achieved at 1 hour post-dose, with ca. 12.4/12.9 μg/ml for 10 mg/kg doses and 76.2/83.7 μg/ml for 50 mg/kg doses in male and female rats, respectively. The plasma concentration of fasiglifam then declined with a half-life (t1/2) of 12.4 hours in males and 11.2 hours in females. The oral bioavailability of fasiglifam was estimated to be between 85-120% in both males and females at both dose levels.

Fasiglifam was the main drug-related compound in plasma, and 15 metabolites, including the acyl glucuronide, were detected. A novel biotransformation was observed that produced a side-chain shortened metabolite via elimination of CH2 from the acetyl side chain. This finding has implications for drug toxicity. Urinary excretion of fasiglifam was low, but female rats eliminated approximately 10-fold more drug-related material by this route than males.

In conclusion, fasiglifam has good oral bioavailability and is extensively metabolized in rats. The pharmacokinetic properties of fasiglifam suggest that it has potential as a treatment for type 2 diabetes, but further studies are needed to determine its safety and efficacy in humans. The sex-related differences in drug elimination also warrant further investigation.