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Human and rat hepatocytes have a strong tendency to underpredict hepatic intrinsic clearance (CL int ) and the extent of underprediction increases with increasing observed CL int In this study, application of the log average rat hepatocyte-rat in vivo empirical scaling factor (ESF) of 4.2 to human hepatocyte prediction successfully removed bias but did not improve precision. An analogous method using individual drug rat ESFs only achieved marginal improvement in accuracy but not precision. A novel approach to resolve clearance-dependent prediction, involving rat ESFs calculated for particular (order of magnitude) ranges of observed CL int (log average range, 0.12-2.1) improved human prediction precision but only modestly reduced bias. However, rat in vivo CL int was several-fold greater than human in vivo CL int and this was reflected in greater rat hepatocyte and microsome CL int , suggesting that rat metabolic enzymes are more efficient than their human counterparts, by several-fold. By applying the segregated rat ESFs followed by the human/rat CL int ratio, which was consistent regardless of CL int (log average 3.5), both accuracy and precision were improved, providing both a means of mitigating clearance dependence and reaffirming the potential role of rat hepatocytes for prediction of human metabolic CL int These cross-species observations indicate that underprediction from human in vitro systems may be predominantly consequential of an intrinsic property of the in vitro system rather than individual drug properties.

drug metabolism and disposition/dmd online

Use of Segregated Hepatocyte Scaling Factors and Cross-Species Relationships to Resolve Clearance Dependence in the Prediction of Human Hepatic Clearance