Evaluation of P-glycoprotein–Mediated Renal Drug Interactions in an MDR1-MDCK Model
AuthorKaryekar, Chetan S.
Eddington, Natalie D.
Garimella, Tushar S.
Gubbins, Paul O.
Dowling, Thomas C.
MetadataShow full item record
AbstractStudy 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-tobasolateral) 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 x 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 x 10-6 cm/second (p<0.05), resulting in a 50% decrease in efflux ratio. Expression of P-gp was negligible in MDCK (wildtype) cells, but high-level expression was confirmed in both MDR1-MDCK and Caco-2 cells. Conclusion. 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.
CitationKaryekar, C. S., Eddington, N. D., Garimella, T. S., Gubbins, P. O., & Dowling, T. C. (2003). Evaluation of P-glycoprotein–Mediated Renal Drug Interactions in an MDR1-MDCK Model. Pharmacotherapy, 23(4), 436-442, DOI: 10.1592/phco.23.4.436.32125.
renal drug interactions--evaluation
ATP-Binding Cassette, Sub-Family B, Member 1
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/689
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