Evaluation of P‐glycoprotein—Mediated Renal Drug Interactions in an MDR1‐MDCK Model

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Abstract
Study Objective. To evaluate P‐glycoprotein (P‐gp)‐mediated renal drug interactions in an in vitro model of tubular secretion.Design. In vitro experiment.Setting. University‐affiliated pharmacokinetics laboratory.Cell Lines. Madin‐Darby canine kidney (MDCK), multidrug‐resistant‐1 (MDR1)‐MDCK, and human colon carcinoma (Caco‐2) cells.Intervention. Transepithelial transport (basolateral‐to‐apical and apical‐to‐basolateral) of cimetidine was assessed in the absence and presence of various concentrations of the P‐gp inhibitors itraconazole and PSC‐833 in a renal P‐gp cell culture model (MDR1‐MDCK).Measurements and Main Results. Apparent permeability of cimetidine was characterized, and level of P‐gp expression was determined by Western blot analysis, in MDCK (wild type), MDR1‐MDCK, and Caco‐2 cells (for relative comparison). In the presence of PSC‐833, cimetidine's apparent permeability value for basolateral‐to‐apical transport decreased from 2.96 to 1.15 times 10−6 cm/second, coupled with a decrease in efflux ratio from 2.36 to 1.80. The effect of itraconazole was concentration dependent, with cimetidine's apparent permeability value for basolateral‐to‐apical transport decreasing from 3.96 to 1.92 times 10−6 cm/second (pConclusion. P‐glycoprotein plays a significant role in the renal tubular secretion of organic cations such as cimetidine, and the high level of P‐gp expression in MDR1‐MDCK cells makes this a well‐suited model for evaluating mechanisms of renal drug interactions.

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