TY - JOUR T1 - Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1080 LP - 1083 VL - 29 IS - 8 AU - Er-jia Wang AU - Christopher N. Casciano AU - Robert P. Clement AU - William W. Johnson Y1 - 2001/08/01 UR - http://dmd.aspetjournals.org/content/29/8/1080.abstract N2 - The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC50 of loratadine (∼11 μM) was ∼160 times the maximum observed plasma concentration (Cmax) following a dose of 10 mg. The IC50 of desloratadine (∼43 μM) was ∼880 times the Cmax following a dose of 5 mg. The positive control, cyclosporin A, had an IC50 of ∼1 μM. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had aVmax about 200% basal activity andKm of ∼3 μM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates. The American Society for Pharmacology and Experimental Therapeutics ER -