title: Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites.
abstract: The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.
authors.affiliation: Drug Metabolism Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka, Japan. hidetaka.kamimura@jp.astellas.com
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nakada
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Ayako
authors.initials: A
authors.lastname: Mera
authors.forename: Kinya
authors.initials: K
authors.lastname: Souda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism; D033161:Government Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D018183:Transplantation Chimera / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D003647:Debrisoquin