In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions
| Autor: | Veronika Rozehnal, Ilona Schreck, Osamu Ando, Tsuneo Deguchi, Chie Makino, Hiroshi Yamazaki, Nobuaki Watanabe, Hideyuki Shiozawa, Akiko Watanabe, Tomoko Ishizuka, Norie Murayama |
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| Rok vydání: | 2018 |
| Předmět: |
Cyclopropanes
Male Agonist medicine.drug_class Health Toxicology and Mutagenesis Metabolite Administration Oral Toxicology 030226 pharmacology & pharmacy Biochemistry Receptors G-Protein-Coupled Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo medicine Animals Humans Anaerobiosis Carbon Radioisotopes Receptor Benzamide Pharmacology Oxadiazoles Chemistry General Medicine Metabolism Macaca fascicularis Metabolic pathway 030220 oncology & carcinogenesis Benzamides Microsome Oxidation-Reduction Metabolic Networks and Pathways |
| DOI: | 10.6084/m9.figshare.7145906.v1 |
| Popis: | A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [14C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated.Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile.DS-8500a was detected at trace levels in urine and bile, demonstrating extensive metabolism prior to urinary/biliary excretion. At least 16 metabolite structures were proposed in plasma, urine, and bile samples from rats treated with [14C]DS-8500a.Formation of a ring-opened metabolite (reduced DS-8500a) in hepatocytes of humans, monkeys, and rats was confirmed; however, it was not affected by typical inhibitors of cytochrome P450s, aldehyde oxidases, or carboxylesterases in human hepatocytes. Extensive formation of the ring-opened metabolite was observed in human liver microsomes fortified with an NADPH-generating system under anaerobic conditions.These results suggest an in vivo unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes. A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [14C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated. Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile. DS-8500a was detected at trace levels in urine and bile, demonstrating extensive metabolism prior to urinary/biliary excretion. At least 16 metabolite structures were proposed in plasma, urine, and bile samples from rats treated with [14C]DS-8500a. Formation of a ring-opened metabolite (reduced DS-8500a) in hepatocytes of humans, monkeys, and rats was confirmed; however, it was not affected by typical inhibitors of cytochrome P450s, aldehyde oxidases, or carboxylesterases in human hepatocytes. Extensive formation of the ring-opened metabolite was observed in human liver microsomes fortified with an NADPH-generating system under anaerobic conditions. These results suggest an in vivo unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes. |
| Databáze: | OpenAIRE |
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