Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein

The absorption of many drugs is affected by their interaction with ATP-bind ing cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that enco des a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using t wo 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 da unorubicin with or without L, DL, and several positive controls. The IC50 o f loratadine (similar to 11 muM) was similar to 160 times the maximum obser ved plasma concentration (C-max) following a dose of 10 mg. The IC50 of des loratadine (similar to 43 muM) was similar to 880 times the C-max following a dose of 5 mg. The positive control, cyclosporin A, had an IC50 of simila r to1 muM. ATP hydrolysis activity was measured in the membrane fraction pr epared from MDR cells presenting P-gp, which were exposed to various concen trations of test compounds. Known substrates of P-gp demonstrated clear, re peatable, concentration-dependent increases in ATP hydrolysis activity. L c aused an increase in ATPase activity above basal levels. L had a V-max abou t 200% basal activity and K-m of similar to3 muM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-g p much less than verapamil or cyclosporin A. DL inhibited human P-gp signif icantly 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 ar e P-gp substrates.