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J Pharm Sci. 2007 Feb;96(2):428-37.

In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver.

Author information

1
Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-1192, Japan.

Abstract

We previously clarified that major human drug metabolizing enzymes were expressed in a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line established recently, in which the liver could be replaced by more than 80% with human hepatocytes. In the present study, we investigated the in vivo drug metabolism of a CYP2D6 substrate, debrisoquin (DB), in chimeric mice with high (High) or low (Low) human albumin (hAlb) concentrations and in control uPA-/-/SCID mice. The hAlb in the mouse blood is one of the indices of humanized liver because the chimeric mice produce hAlb. After oral administration of DB at 2.0 mg/kg, the AUC0-8 value of a major CYP2D6 metabolite of DB, 4'-hydroxydebrisoquin (4-OH DB), in High was 3.6-fold higher than those of Low and uPA-/-/SCID mice. By pre-treatment with a typical CYP2D6 inhibitor, quinidine, the AUC0-8 value of 4-OH DB in High was decreased although such values in Low and uPA-/-/SCID mice did not change. The in vitro kinetic analyses and the Ki values of quinidine on the DB 4'-hydroxylase activity in liver microsomes also supported the humanization of the chimeric mice. In conclusion, the chimeric mice exhibited a humanized profile of drug metabolism and the inhibition of P450.

PMID:
17051594
DOI:
10.1002/jps.20783
[Indexed for MEDLINE]

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