The aim of this study was to explore potential transport mechanisms of cetirizine enantiomers across Caco-2 cells. Cetirizine displayed polarized transport at concentrations ranging from 4.0 to 80.0 microM, with the permeability in the secretory direction being 1.4- to 4.0-fold higher than that in the absorptive direction. Cetirizine enantiomers were transported distinctively different from each other. In the presence of inhibitors of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), the absorptive transport was enhanced and secretory efflux was diminished. When verapamil, indomethacin, or probenecid were present, the difference in the absorptive permeability of R-cetirizine and S-cetirizine substantially intensified, whereas quinidine could eliminate. R-cetirizine significantly increased the efflux ratio of rhodamine-123 and doxorubicin in a fashion indicative of the upregulation of P-gp and MRP activities. However, S-cetirizine played a role of an inhibitor for P-gp and MRP. Ranitidine modified the absorption of cetirizine enantiomers, suggesting that the potential drug-drug interaction would significantly change the cetirizine pharmacokinetics. In conclusion, the results indicated that there are several efflux transporters including P-gp and MRP participating the absorption and efflux of cetirizine, which showed enantioselectivity in the transmembrane process. In addition, both P-gp and MRP functions could be modulated by cetirizine in chiral discriminative ways.
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