<i>In vivo</i> 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
Creators: name: Makino, Chie
name: Watanabe, Akiko
name: Deguchi, Tsuneo
name: Shiozawa, Hideyuki
name: Schreck, Ilona
name: Rozehnal, Veronika
name: Ishizuka, Tomoko
name: Watanabe, Nobuaki
name: Ando, Osamu
name: Murayama, Norie
name: Yamazaki, Hiroshi
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biochemistry
subject: Medicine
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: Evolutionary Biology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Marine Biology
subject: Cancer

description: A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. <i>In vivo</i> metabolic fates of [<sup>14</sup>C]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 [<sup>14</sup>C]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 <i>in vivo</i> 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. <i>In vivo</i> metabolic fates of [<sup>14</sup>C]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 [<sup>14</sup>C]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 <i>in vivo</i> unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes.