Drug Metabolism and Pharmacokinetics Research Laboratories (A.K., Y.M., A.M., T.E., Y.T.) and Drug Safety Research Laboratories (I.M., H.F.), Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan; Takeda Development Center Americas, Inc., Deerfield, Illinois (L.P.); and Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California (L.Z.B.)
Drug Metabolism and Pharmacokinetics Research Laboratories (A.K., Y.M., A.M., T.E., Y.T.) and Drug Safety Research Laboratories (I.M., H.F.), Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan; Takeda Development Center Americas, Inc., Deerfield, Illinois (L.P.); and Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California (L.Z.B.).
Drug Metab Dispos. 2019 May;47(5):525-534. doi: 10.1124/dmd.118.084889. Epub 2019 Feb 14.
Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts. These histopathological changes were not observed in rat toxicology studies. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of dog liver sections obtained from a repeat-dose toxicology study indicated that the crystalline material in the affected dog liver contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Nonclinical mechanistic studies indicated that after 14 days of repeated oral dosing with [C]fasiglifam at 200 mg/kg per day to dogs, the concentrations of fasiglifam and fasiglifam-G in the bile exceeded the solubility limit of these compounds in the bile (approximately 3000 g/ml). After single oral 2- and 200-mg/kg doses administered to rats and dogs, fasiglifam and fasiglifam-G concentrations in dog bile were 5- to 10-fold higher than those in rat bile for the same dose of fasiglifam, while the bile flow rate adjusted by body weight was 4- to 8-fold lower in dogs than in rats. High fasiglifam and fasiglifam-G concentrations in dog bile together with lower bile flow rate could cause crystal formation in dog bile, resulting in secondary granulomatous inflammation in the dog liver.
法西格列汀是一种作用于 G 蛋白偶联受体 40 的高效、高选择性激动剂，原研用于治疗 2 型糖尿病。然而，由于肝安全性问题，其 III 期临床试验被终止。在重复剂量犬毒理学研究中也观察到与法西格列汀相关的肝毒性，表现为肝脏和/或胆管内有肉芽肿性炎症伴结晶形成。在大鼠毒理学研究中未观察到这些组织病理学变化。来自重复剂量毒理学研究的犬肝组织切片的基质辅助激光解吸/电离飞行时间质谱分析表明，受影响犬肝脏中的结晶物质含有法西格列汀和法西格列汀葡萄糖醛酸苷（法西格列汀-G）。非临床机制研究表明，在连续 14 天每天以 200mg/kg 的剂量给犬重复口服[C]法西格列汀后，胆汁中法西格列汀和法西格列汀-G 的浓度超过了这些化合物在胆汁中的溶解度极限（约 3000g/ml）。在大鼠和犬单次口服 2 毫克/千克和 200 毫克/千克剂量后，相同剂量的法西格列汀在犬胆汁中的法西格列汀和法西格列汀-G 浓度比在大鼠胆汁中的浓度高 5-10 倍，而犬胆汁的胆汁流速按体重调整比大鼠低 4-8 倍。犬胆汁中高浓度的法西格列汀和法西格列汀-G 与较低的胆汁流速可能导致犬胆汁结晶形成，导致犬肝脏继发性肉芽肿性炎症。
