Predictability of plasma concentration-time curves in humans using single-species allometric scaling of chimeric mice with humanized liver.
1. We used chimeric mice (PXB mice®), which were repopulated with human hepatocytes, to evaluate their predictabilities of human pharmacokinetics. 2. The relationships of total clearance (CLt) and the volume of distribution at steady state (Vdss) between that predicted from single-species allometric scaling (SSS) of PXB mice and the observed human values indicated good correlations for various drugs metabolized by cytochrome P450s (CYPs) and non-CYPs. 3. We examined the Dedrick plot with which the plasma concentration-time curves can exhibit superimposability using SSS of PXB mice for CLt and Vdss. The predicted plasma concentration-time curves using the complex Dedrick plot from PXB mice were generally superimposed with the observed human data. 4. However, the predicted curve of diazepam was not superimposable with the observed profile. Residual mouse hepatocytes in the livers of PXB mice may affect predictability of CLt of diazepam because significant discrepancy of in vitro intrinsic clearance in PXB mouse liver microsomes consisted of low and high replacement of human hepatocytes were observed. 5. The complex Dedrick plot with SSS from PXB mice is useful for predicting the plasma concentration-time curve in drug discovery, although there are some limitations.
Graduate School of Biomedical & Health Sciences, Hiroshima University , Hiroshima , Japan .
Seigo
S
Sanoh
Yoichi
Y
Naritomi
Mami
M
Fujimoto
Koya
K
Sato
Akio
A
Kawamura
Aya
A
Horiguchi
Kazumi
K
Sugihara
Yaichiro
Y
Kotake
Hiroki
H
Ohshita
Chise
C
Tateno
Toru
T
Horie
Shigeyuki
S
Kitamura
Shigeru
S
Ohta
D000818:Animals; D002675:Child, Preschool; D002678:Chimera; D006801:Humans; D008099:Liver; D008297:Male; D051379:Mice; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
D004364:Pharmaceutical Preparations
Chimeric humanized mice; Dedrick plot; hepatocytes; pharmacokinetics; prediction; single-species allometric scaling