Evaluation of P-glycoprotein–Mediated Renal Drug Interactions in an MDR1-MDCK Model
dc.contributor.author | Karyekar, Chetan S. | |
dc.contributor.author | Eddington, Natalie D. | |
dc.contributor.author | Garimella, Tushar S. | |
dc.contributor.author | Gubbins, Paul O. | |
dc.contributor.author | Dowling, Thomas C. | |
dc.date.accessioned | 2011-11-16T13:53:30Z | |
dc.date.available | 2011-11-16T13:53:30Z | |
dc.date.issued | 2003 | |
dc.identifier.citation | Karyekar, 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. | en_US |
dc.identifier.issn | 0277-0008 | |
dc.identifier.uri | http://hdl.handle.net/10713/689 | |
dc.description.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-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. | en_US |
dc.language.iso | en_US | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.subject | p-glycoprotein | en_US |
dc.subject | renal drug interactions--evaluation | en_US |
dc.subject.mesh | ATP-Binding Cassette, Sub-Family B, Member 1 | en_US |
dc.subject.mesh | Drug Interactions | en_US |
dc.subject.mesh | Kidney | en_US |
dc.title | Evaluation of P-glycoprotein–Mediated Renal Drug Interactions in an MDR1-MDCK Model | en_US |
dc.type | Article | en_US |
refterms.dateFOA | 2019-02-19T17:06:13Z |