title: In vitro and in vivo metabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver.
abstract: 1. A novel oral chymase inhibitor, SUN13834, is under clinical development for the treatment of atopic dermatitis (AD). In this study, in vitro and in vivo metabolic profiles of SUN13834 were compared between severe combined immunodeficiency (SCID) mice, chimeric mice with humanized liver and humans. 2. In in vitro experiments using liver microsomes, predominant metabolites of SUN13834 were glucuronide (MG-1) in SCID mice and hydroxylated metabolite (M-3) in chimeric mice and humans. 3. After a single oral dose of [(14)C]SUN13834 to SCID and chimeric mice, glucuronidation was the major metabolic pathway in SCID mice, while the parent compound, ring opening form (M-5), O-demethylated form of M-5 (M-6) and glucuronidation of M-6 (M-6G) were detected at higher levels in chimeric mice compared to SCID mice. 4. When AD patients were orally treated using SUN13834 for 28 days, the parent compound had the highest concentration in plasma, and M-6, M-6G, M-5 and MG-1 were identified as major metabolites. 5. This is the first report of SUN13834 metabolic information in human. In addition, based on similarities in metabolic profiles between chimeric mice and humans, it was concluded that chimeric mice are useful for predicting SUN13834 metabolism in humans during early stages of drug development.
authors.affiliation: Faculty of Safety & ADME, Asubio Pharma Co., Ltd. , Hyogo , Japan and.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Igawa
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Fujitani
authors.forename: Bharti
authors.initials: B
authors.lastname: Shah
authors.forename: Charles
authors.initials: C
authors.lastname: Oo
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000818:Animals; D001381:Azepines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D053818:Chymases / Q000037:antagonists & inhibitors; D003876:Dermatitis, Atopic / Q000097:blood / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018183:Transplantation Chimera
chemical_list: C538783:6-(5-chloro-2-methoxybenzyl)-4-alarkylaminocarbonyl-1,4-diazepane-2,5-dione; D001381:Azepines; D004791:Enzyme Inhibitors; D020719:Glucuronides; D053818:Chymases