Prediction of Hepatic Efflux Transporter-Mediated Drug Interactions: When Is it Optimal to Measure Intracellular Unbound Fraction of Inhibitors?

The intracellular unbound inhibitor concentration ([I] _unbound,cell ) is the most relevant concentration for predicting the inhibition of hepatic efflux transporters. However, the intracellular unbound fraction of inhibitor in hepatocytes (f _{u,cell,inhibitor} ) is not routinely determined. Studies are needed to evaluate the benefit of measuring f _{u,cell,inhibitor} and using [I] _unbound,cell versus intracellular total inhibitor concentration ([I] _total,cell ) when predicting inhibitory effects. This study examined the benefit of using [I] _unbound,cell to predict hepatocellular bile acid disposition. Cellular total concentrations of taurocholate ([TCA] _total,cell ), a prototypical bile acid, were simulated using pharmacokinetic parameters estimated from sandwich-cultured human hepatocytes. The effect of various theoretical inhibitors was simulated by varying ([I] _total,cell / half maximal inhibitory concentration [IC ₅₀ ]) values. In addition, the fold change was calculated as the simulated [TCA] _total,cell when f _{u,cell,inhibitor}  = 1 divided by the simulated [TCA] _total,cell when f _{u,cell,inhibitor}  = 0.5-0.01. The lowest ([I] _total,cell /IC ₅₀ ) value leading to a >2-fold change in [TCA] _total,cell was chosen as a cutoff, and a framework was developed to categorize risk inhibitors for which the measurement of f _{u,cell,inhibitor} is optimal. Fifteen compounds were categorized, 5 of which were compared with experimental observations. Future work is needed to evaluate this framework based on additional experimental data. In conclusion, the benefit of measuring f _{u,cell,inhibitor} to predict hepatic efflux transporter-mediated drug-bile acid interactions can be determined a priori.
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