Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism
| Autor: | David S. Wagner, Vishal Shah, J. Sigafoos, Russell L. Yeager, Steve Castellino, Gary D Bowers, Gary Boyle, Mark de Serres, Andrew D. Roberts, Mehul Dave, Claire Beaumont, Katie L Olson, Cosette J. Serabjit-Singh, Dipak K. Patel |
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| Rok vydání: | 2011 |
| Předmět: |
Drug
Male Pyrrolidines Health Toxicology and Mutagenesis Metabolite media_common.quotation_subject Phenylalanine Mice SCID Biology Pharmacology Toxicology Biochemistry Models Biological chemistry.chemical_compound Benzophenones Mice Tetrahydroisoquinolines Animals Humans media_common Sulfonamides Drug discovery Tetrahydroisoquinoline Chimera General Medicine Metabolism Drug development chemistry Liver Pharmaceutical Preparations Renal physiology Female Drug metabolism |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 41(6) |
| ISSN: | 1366-5928 |
| Popis: | A model that predicts human metabolism and disposition of drug candidates would be of value in early drug development. In this study, a chimeric (uPA+/+)/SCID mouse model was evaluated with three structurally distinct compounds (GW695634, a benzophenone, SB-406725, a tetrahydroisoquinoline and GW823093, a fluoropyrrolidine) for which human metabolism and disposition was characterized. Human metabolite profiles in plasma and/or urine were compared to those of chimeric (uPA+/+)/SCID and control CD-1 or (uPA+/+)/SCID) mice. GW695634 and SB-406725 exhibited primarily hepatic metabolism and were chosen as probes to assess which human metabolites would likely circulate systemically. GW823093 exhibited a combination of hepatic and extrahepatic metabolism such that renal excretion of drug-related material was ~2-fold greater in humans than in mice, and thus chosen as a probe to assess if the chimeric (uPA+/+)/SCID mouse would predict the urinary excretion of human metabolites. We observed that human metabolism and disposition was well represented for GW695634, somewhat represented for GW823093 and minimally represented for SB-406725. Collectively, the results of this and other studies suggest that while limitations for prediction of human metabolism and disposition exist, humanized chimeric mouse models can potentially represent informative new tools in drug discovery and development. |
| Databáze: | OpenAIRE |
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