Figure 1

Schematic drawing of the models and the inhibitor concentrations used in the DDI predictions. (a) Time-dependent inhibitors can alter the activity of CYP3A in both intestine and liver. Measured or estimated total and unbound inhibitor concentrations in blood are commonly used as surrogates for the inhibitor concentrations affecting CYP3A inside cells. More realistic estimates of the intracellular unbound concentrations affecting CYP3A are obtained by correcting these concentrations for intracellular (F_ic) or cytosolic bioavailability (F_cyto). (b) Difference between F_ic and F_cyto. CYP3A is located in the endoplasmic reticulum with its binding sites facing the cytosol. As the pH inside lysosomes is below that of the cytosol, basic lipophilic compounds tend to get trapped in the lysosomes. Since F_ic also includes drugs in the acidic endo-lysosomal compartment, F_ic (left) gives an overestimation of the basic lipophilic inhibitor compound available at the active site of CYP3A. F_cyto (right), is determined in the presence of chloroquine, which increases the lysosomal pH and eliminates the trapping of bases inside acidic compartments. As drugs access CYP3A from the cytosol, correction for F_cyto gives a better estimate than F_ic of the actual unbound drug concentration binding to the enzyme. F_cyto, cytosolic bioavailability; F_ic, intracellular bioavailability; [I]_ave,u, unbound average inhibitor concentration; [I]_g, intestinal inhibitor concentration; [I]_inlet,ave,u, unbound hepatic inlet inhibitor concentration based on [I]_ave; [I]_inlet,max,u, unbound hepatic inlet inhibitor concentration based on [I]_max; [I]_max,u, unbound peak inhibitor concentration; P450, cytochrome P450.