{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T19:59:26Z","timestamp":1783022366078,"version":"3.54.6"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,1,26]],"date-time":"2016-01-26T00:00:00Z","timestamp":1453766400000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chimeric mice with humanized livers (PXB mice) are used to investigate the metabolism and pharmacokinetics of drugs in humans. However, residual murine enzymatic activities derived from the liver and the presence of mouse small intestinal metabolism can hamper the prediction of human drug metabolism. Recently murine<jats:italic>Cytochrome P450 3a<\/jats:italic>gene knockout chimeric mice with humanized livers (<jats:italic>Cyp3a<\/jats:italic>KO CM) were developed. To evaluate the prediction of drug metabolism, nefazodone (NEF) was administered orally at 10 mg\/kg to the following mouse strains:<jats:italic>Cyp3a<\/jats:italic>KO CM, murine<jats:italic>Cyp3a<\/jats:italic>gene knockout (<jats:italic>Cyp<\/jats:italic>3a KO), PXB and severe combined immunodeficiency (SCID) mice. Liquid chromatography\u2010mass spectrometry was used for metabolic profiling of plasma, urine and bile. The prediction of human metabolite levels such as hydroxy nefazodone (OH\u2010NEF), triazoledione form (TD),<jats:italic>m<\/jats:italic>\u2010chlorophenylpiperazine and dealkyl metabolites in<jats:italic>Cyp3a<\/jats:italic>KO CM was superior to that in<jats:italic>Cyp3a<\/jats:italic>KO, PXB or SCID mice. Further, clinical exposure levels of NEF, OH\u2010NEF and TD were reproduced in<jats:italic>Cyp3a<\/jats:italic>KO CM. In contrast, NEF was rapidly metabolized to TD in both PXB and SCID mice but not in<jats:italic>Cyp3a<\/jats:italic>KO mice, suggesting that murine CYP3A is involved in the elimination of NEF in these mice. These findings demonstrate that the metabolic profile of NEF in<jats:italic>Cyp3a<\/jats:italic>KO CM differs qualitatively and quantitatively from that in PXB mice due to the higher metabolic rate of NEF and its metabolites via murine CYP3A. Therefore<jats:italic>Cyp3a<\/jats:italic>KO CM might be useful in predicting the metabolic profiles of drug candidates in humans. Copyright \u00a9 2016 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.1990","type":"journal-article","created":{"date-parts":[[2015,9,9]],"date-time":"2015-09-09T19:31:06Z","timestamp":1441827066000},"page":"3-14","source":"Crossref","is-referenced-by-count":16,"title":["Murine<i>Cyp3a<\/i>knockout chimeric mice with humanized liver: prediction of the metabolic profile of nefazodone in humans"],"prefix":"10.1002","volume":"37","author":[{"given":"Naoyuki","family":"Nakada","sequence":"first","affiliation":[{"name":"Drug Metabolism Research Laboratories, Drug Discovery Research Astellas Pharma Inc. Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Drug Metabolism Research Laboratories, Drug Discovery Research Astellas Pharma Inc. 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