Prediction of human disposition toward S-3H-warfarin using chimeric mice with humanized liver.
Chimeric mice, constructed by transplanting human hepatocytes, are useful for predicting the human metabolism of drug candidates. In this study, we investigated whether these mice show similar metabolic profile to humans by examining the hydroxylation of S-warfarin reported to be mainly metabolized to S-7-hydroxywarfarin (7-OH-warfarin), catalyzed by CYP2C9, in humans. When S-(3)H-warfarin was administered to chimeric mice and control (uPA(+/+)/SCID(wt/wt)) mice, the blood concentration-time curve was higher in chimeric than control mice. Plasma protein binding of S-(3)H-warfarin of chimeric and control mice amounted to 98.1 and 92.1%, respectively. When S-(3)H-warfarin was administered to these mice, radioactivity was mainly recovered in urine (81.7% in chimeric mice and 65.9% in control mice). After S-(3)H-warfarin was administered to these mice, the radioactivity was recovered in the bile of chimeric and control mice at 5.1 and 17.9%, respectively. The main urinary metabolite in chimeric mice was 7-OH-warfarin. the main urinary metabolite in control mice was S-4'-hydroxywarfarin. These results show that mass balance, metabolic disposition of S-(3)H-warfarin in chimeric mice with humanized liver were similar to reported human data.
Inoue
Tae
T
Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Sugihara
Kazumi
K
Ohshita
Hiroki
H
Horie
Toru
T
Kitamura
Shigeyuki
S
Ohta
Shigeru
S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D002678:Chimera / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014859:Warfarin / Q000031:analogs & derivatives* / Q000378:metabolism
C101436:8-hydroxywarfarin; D014859:Warfarin; C087837:7-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases