Vol. 29, Issue 8, 1080-1083, August 2001

Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein

Er-jia Wang, Christopher N. Casciano, Robert P. Clement, and William W. Johnson

Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, New Jersey

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 (C_max) following a dose of 10 mg. The IC₅₀ of desloratadine (~43 µM) was ~880 times the C_max 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 a V_max about 200% basal activity and K_m 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.