Evaluation of P-glycoprotein-mediated renal drug interactions in an MDR1-MDCK model.
OBJECTIVE
To evaluate P-glycoprotein (P-gp)-mediated renal drug interactions in an in vitro model of tubular secretion.


METHODS
In vitro experiment.


METHODS
University-affiliated pharmacokinetics laboratory. CELL LINES: Madin-Darby canine kidney (MDCK), multidrug-resistant-1 (MDR1)-MDCK, and human colon carcinoma (Caco-2) cells.


METHODS
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).


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.


CONCLUSIONS
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.
Karyekar
Chetan S
CS
Pharmacokinetics-Biopharmaceutics Laboratory, School of Pharmacy, University of Maryland, Baltimore 21201, USA.
Eddington
Natalie D
ND
Garimella
Tushar S
TS
Gubbins
Paul O
PO
Dowling
Thomas C
TC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D002460:Cell Line; D002927:Cimetidine / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000493:pharmacokinetics; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D017964:Itraconazole / Q000493:pharmacokinetics; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D017964:Itraconazole; D002927:Cimetidine; C070272:valspodar