title: Stereoselective and multiple carrier-mediated transport of cetirizine across Caco-2 cell monolayers with potential drug interaction.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017332:Cetirizine / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013379:Substrate Specificity; D013696:Temperature
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D017332:Cetirizine; D027425:ATP-Binding Cassette, Sub-Family C Proteins