In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver.
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.
Katoh
Miki
M
Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-1192, Japan.
Sawada
Toshiro
T
Soeno
Yoshinori
Y
Nakajima
Miki
M
Tateno
Chise
C
Yoshizato
Katsutoshi
K
Yokoi
Tsuyoshi
T
D018663:Adrenergic Agents / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D002678:Chimera; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003647:Debrisoquin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D017374:Paroxetine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics
D018663:Adrenergic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017374:Paroxetine; C012359:4-hydroxydebrisoquin; D019389:Cytochrome P-450 CYP2D6; D014568:Urokinase-Type Plasminogen Activator; D011802:Quinidine; D003647:Debrisoquin