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Xenobiotica. 2015;45(7):605-14. doi: 10.3109/00498254.2015.1007112. Epub 2015 Mar 3.

Predictability of plasma concentration-time curves in humans using single-species allometric scaling of chimeric mice with humanized liver.

Author information

1
Graduate School of Biomedical & Health Sciences, Hiroshima University , Hiroshima , Japan .

Abstract

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.

KEYWORDS:

Chimeric humanized mice; Dedrick plot; hepatocytes; pharmacokinetics; prediction; single-species allometric scaling

PMID:
25733030
DOI:
10.3109/00498254.2015.1007112
[Indexed for MEDLINE]

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