Evaluation of P-glycoprotein-mediated renal drug interactions in an MDR1-MDCK model.

Autor: Karyekar CS; Pharmacokinetics-Biopharmaceutics Laboratory, School of Pharmacy, University of Maryland, Baltimore 21201, USA., Eddington ND, Garimella TS, Gubbins PO, Dowling TC
Jazyk: angličtina
Zdroj: Pharmacotherapy [Pharmacotherapy] 2003 Apr; Vol. 23 (4), pp. 436-42.
DOI: 10.1592/phco.23.4.436.32125
Abstrakt: 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 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 (wild-type) 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.
Databáze: MEDLINE
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