P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies.

摘要: Many P-glycoprotein (P-gp) inhibitors studied in vitro and vivo are also known or suspected to be substrates and/or of cytochrome P-450 3A (CYP3A). Such overlap raises the question whether CYP3A inhibition is an intrinsic characteristic P-gp inhibitors, a matter concern development rational use such agents. Thus, purpose present study was determine ability inhibit is, fact, linked specific with limited can identified. Therefore, potency series 14 assessed by measuring their transepithelial flux across Caco-2 cells digoxin, prototypical substrate. determined from impairment nifedipine oxidation human liver microsomes. Determination apparent Ki values for IC50s allowed comparison relative inhibitory compounds on two proteins' function. The ranged 0.04 3.8 microM. All inhibited between 0.3 76 microM 1.5 50 However, no correlation found extent inhibition, ratio IC50 varied 1.1 125. These results demonstrate that, although many potent CYP3A, varying degree selectivity present. minimal absent effects should decrease impact drug interactions therapeutic compounds.