Stereoselective and multiple carrier‐mediated transport of cetirizine across Caco‐2 cell monolayers with potential drug interaction

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.