P-Glycoprotein and Cytochrome P-450 3A Inhibition: Dissociation of Inhibitory Potencies

Many P-glycoprotein (P-gp) inhibitors studied in vitro and in vivo are also known or suspected to be substrates and/or inhibitors of cytochrome P-450 3A (CYP3A). Such overlap raises the question of whether CYP3A inhibition is an intrinsic characteristic of P-gp inhibitors, a matter of concern in the development and rational use of such agents. Thus, the purpose of the present study was to determine whether the ability to inhibit P-gp and CYP3A is, in fact, linked and whether specific P-gp inhibitors with limited ability to inhibit CYP3A can be identified. Therefore, the potency of a series of 14 P-gp inhibitors was assessed by measuring their inhibition of the transepithelial flux across Caco-2 cells of digoxin, a prototypical P-gp substrate. CYP3A inhibition was determined from the impairment of nifedipine oxidation by human liver microsomes. Determination of the apparent K i values for CYP3A inhibition and the IC 50 s for P-gp and CYP3A inhibition allowed comparison of the relative inhibitory potency of the compounds on the two proteins’ function. The IC 50 s for P-gp inhibition ranged from 0.04 to 3.8 μm. All compounds inhibited CYP3A with apparent K i values of between 0.3 and 76 μm and IC 50 s between 1.5 and 50 μm. However, no correlation was found between the extent of P-gp inhibition and CYP3A inhibition, and the ratio of the IC 50 for CYP3A inhibition to the IC 50 for P-gp inhibition varied from 1.1 to 125. These results demonstrate that, although many P-gp inhibitors are potent inhibitors of CYP3A, a varying degree of selectivity is present. The development and use of P-gp inhibitors with minimal or absent CYP3A inhibitory effects should decrease the impact of drug interactions on the therapeutic use of such compounds.