Prediction of Human Hepatic Clearance for Cytochrome P450 Substrates <i>via</i> a New Culture Method Using the Collagen Vitrigel Membrane Chamber and Fresh Hepatocytes Isolated from Liver Humanized Mice

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<p>In drug discovery, hepatocytes have been widely utilized as <i>in vitro</i> tools for predicting the <i>in vivo</i> hepatic clearance (<i>CL</i>) of drug candidates. However, conventional hepatocyte models do not always reproduce <i>in vivo</i> physiological function, and CYP activities in particular decrease quite rapidly during culture. Furthermore, conventional <i>in vitro</i> assays have limitations in their ability to predict hepatic <i>CL</i> of metabolically stable drug candidates. In order to accurately predict hepatic <i>CL</i> of candidate drugs, a new method of culturing hepatocytes that activates their functional properties, including CYP activities, is in high demand. In the previous study, we established a novel long-term culture method for PXB-cells<sup>®</sup> using a collagen vitrigel membrane (CVM) chamber, which can maintain CYP activity and liver specific functions at high levels for several weeks. In this study, the vitrigel culture method was applied to predictions of hepatic <i>CL</i> for 22 CYP typical substrates with low to middle <i>CL</i>, and the prediction accuracy by this method was assessed by comparing <i>CL</i> data between predicted (<i>in vitro</i> intrinsic <i>CL</i> using the dispersion model) and observed (<i>in vivo</i> clinical data) values. The results of this study showed that <i>in vitro</i> <i>CL</i> values for approximately 60% (13/22) and 80% (18/22) of the compounds were predicted within a 2- and 3-fold difference with <i>in vivo</i> <i>CL</i>, respectively. These results suggest that the new culture method using the CVM chamber and PXB-cells is a promising <i>in vitro</i> system for predicting human hepatic <i>CL</i> with high accuracy for CYP substrates, including metabolically stable drug candidates.</p>


  • Biological and Pharmaceutical Bulletin

    Biological and Pharmaceutical Bulletin 42(3), 348-353, 2019

    The Pharmaceutical Society of Japan


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