UCSF

Purpose

To examine the theoretical/practical utility of the liver-to-blood partition coefficient (Kp_uu) for predicting drug-drug interactions (DDIs), and compare the Kp_uu-approach to the extended clearance concept AUC_R-approach.

Methods

The Kp_uu relationship was derived from first principles. Theoretical simulations investigated the impact of changes in a single hepatic-disposition process on unbound systemic (AUC_B,u) and hepatic exposure (AUC_H,u) versus Kp_uu. Practical aspects regarding Kp_uu utilization were examined by predicting the magnitude of DDI between ketoconazole and midazolam employing published ketoconazole Kp_uu values.

Results

The Kp_uu hepatic-disposition relationship is based on the well-stirred model. Simulations emphasize that changes in influx/efflux intrinsic clearances result in Kp_uu changes, however AUC_H,u remains unchanged. Although incorporation of Kp_uu is believed to improve DDI-predictions, utilizing published ketoconazole Kp_uu values resulted in prediction errors for a midazolam DDI.

Conclusions

There is limited benefit in using Kp_uu for DDI-predictions as the AUC_R-based approach can reasonably predict DDIs without measurement of intracellular drug concentrations, a difficult task hindered by experimental variability. Further, Kp_uu changes can mislead as they may not correlate with changes in AUC_B,u or AUC_H,u. The well-stirred model basis of Kp_uu when applied to hepatic-disposition implies that nuances of intracellular drug distribution are not considered by the Kp_uu model.