Kogame Akifumi, Lee Ronald, Pan Liping, Sudo Miyako, Nonaka Masami, Moriya Yuu, Higuchi Tomoaki, Tagawa Yoshihiko
a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division , Takeda Pharmaceutical Company Limited , Fujisawa , Kanagawa , Japan.
b Takeda Development Center Americas, Inc. , Deerfield , IL , USA.
Xenobiotica. 2019 Apr;49(4):433-445. doi: 10.1080/00498254.2018.1453100. Epub 2018 Apr 5.
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 [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.
在大鼠、犬和人类中对法格列净的吸收、分布、代谢及排泄情况进行了研究。法格列净在所有物种中的绝对口服生物利用度均较高（>76.0%）。口服[C]法格列净后，给药放射性物质可被定量回收，且在所有物种中，放射性物质的主要排泄途径均为粪便。法格列净是所有物种血浆和粪便中的主要成分。其氧化代谢物（M-I）在大鼠和人类血浆中作为次要代谢物被观察到（<血浆放射性的10%）。在人类血浆中，羟基化法格列净（T-1676427）、法格列净的葡萄糖醛酸苷（法格列净-G）以及M-I的葡萄糖醛酸苷被检测为另外的次要代谢物（<血浆放射性的2%）。这些代谢物均非人类所特有。法格列净-G是大鼠和犬胆汁中的主要成分。体外细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）反应表型分析表明，法格列净的氧化（形成M-I和T-1676427）和葡萄糖醛酸化分别主要由CYP3A4/5和UGT1A3介导。法格列净和法格列净-G分别是乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白2（Mrp2/MRP2）的底物。在包括人类在内的所有受试物种中，法格列净-G的葡萄糖醛酸化被发现是法格列净的主要消除途径。
