Disposition and metabolism of the G protein-coupled receptor 40 agonist TAK-875 (fasiglifam) in rats, dogs, and humans. (3rd April 2019)

• Record Type: Journal Article
• Authors: Kogame, Akifumi; Lee, Ronald; Pan, Liping; Sudo, Miyako; Nonaka, Masami; Moriya, Yuu; Higuchi, Tomoaki; Tagawa, Yoshihiko
• Is Part Of: Xenobiotica. Volume 49:Number 4(2019:Apr.)
• Page Start: 433
• Page End: 445
• Publication Date: 2019-04-03
• Subjects: TAK-875 -- fasiglifam -- G protein-coupled receptor 40 -- disposition -- metabolite profiling -- pharmacokinetics -- LC/MS; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2018.1453100
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: The absorption, distribution, metabolism, and excretion of fasiglifam were investigated in rats, dogs, and humans. The absolute oral bioavailability of fasiglifam was high in all species (>76.0%). After oral administration of [ 14 C]fasiglifam, the administered radioactivity was quantitatively recovered and the major route of excretion of radioactivity was via feces in all species. Fasiglifam was a major component in the plasma and feces in all species. Its oxidative metabolite (M-I) was observed as a minor metabolite in rat and human plasma (<10% of plasma radioactivity). In human plasma, hydroxylated fasiglifam (T-1676427), the glucuronide of fasiglifam (fasiglifam-G), and the glucuronide of M-I were detected as additional minor metabolites (<2% of plasma radioactivity). None of these metabolites were specific to humans. Fasiglifam-G was the major component in the rat and dog bile. In vitro cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) reaction phenotyping indicated that oxidation (to form M-I and T-1676427) and glucuronidation of fasiglifam are mainly mediated by CYP3A4/5 and UGT1A3, respectively. Fasiglifam and fasiglifam-G are substrates of BCRP and Mrp2/MRP2, respectively. Glucuronidation of fasiglifam-G was found to be the predominant elimination pathway of fasiglifam in all species tested, including humans.