Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling
| Autor: | Amit S. Kalgutkar, Shinichi Ninomiya, Satoshi Ito, Hidetaka Kamimura, Marina Mitsui, Sho Nishinoaki, Yosuke Yamamoto, Tomohiro Ishiguro, Hiroshi Yamazaki, Takeshi Okuzono, Hiroyuki Chijiwa, Hiroshi Suemizu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Drug
Health Toxicology and Mutagenesis media_common.quotation_subject Metabolite Pharmacology Toxicology 030226 pharmacology & pharmacy Biochemistry Models Biological 03 medical and health sciences Chimera (genetics) chemistry.chemical_compound Mice 0302 clinical medicine Pharmacokinetics Glucokinase medicine Animals Humans media_common Benzofurans biology Chimera Cytochrome P450 General Medicine Metabolism Hyperplasia medicine.disease Pyrimidines chemistry 030220 oncology & carcinogenesis biology.protein Hepatocytes |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 47(5) |
| ISSN: | 1366-5928 |
| Popis: | 1. The partial glucokinase activator N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319) is biotransformed in humans to N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (M1), accounting for ∼65% of total exposure at steady state. 2. As the disproportionately abundant nature of M1 could not be reliably predicted from in vitro metabolism studies, we evaluated a chimeric mouse model with humanized liver on TK-NOG background for its ability to retrospectively predict human disposition of PF-04937319. Since livers of chimeric mice were enlarged by hyperplasia and contained remnant mouse hepatocytes, hepatic intrinsic clearances normalized for liver weight, metabolite formation and liver to plasma concentration ratios were plotted against the replacement index by human hepatocytes and extrapolated to those in the virtual chimeric mouse with 100% humanized liver. 3. Semi-physiological pharmacokinetic analyses using the above parameters revealed that simulated concentration curves of PF-04937319 and M1 were approximately superimposed with the observed clinical data in humans. 4. Finally, qualitative profiling of circulating metabolites in humanized chimeric mice dosed with PF-04937319 or M1 also revealed the presence of a carbinolamide metabolite, identified in the clinical study as a human-specific metabolite. The case study demonstrates that humanized chimeric mice may be potentially useful in preclinical discovery towards studying disproportionate or human-specific metabolism of drug candidates. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|