Transport characteristics of ebastine and its metabolites across human intestinal epithelial Caco-2 cell monolayers

The transport characteristics of a selective peripheral H-1 receptor antago nist, ebastine, a substrate for cytochrome P450 3A4, and its three major me tabolites, i.e., the hydroxy metabolite of ebastine (M-OH), the pharmacolog ically active metabolite carebastine (Car), and the desbutyrophenone metabo lite (des-BP), were studied in cultured human intestinal Caco-2 cells expre ssing a drug efflux pump, P-glycoprotein (P-gp), on the apical membrane. Th e polarized transport of [H-3]cyclosporin A (CyA), mediated by P-gp in the basolateral to apical direction across the Caco-2 cell monolayers, was affe cted by the presence of ebastine in a concentration-dependent manner and si gnificant inhibition was observed at high concentrations (>50 muM). M-OH (3 00 muM) also significantly inhibited whereas Car and des-BP did not. Althou gh no marked polarized transport of [C-14]ebastine in a secretory direction was observed in the Caco-2 systems, the flux in the basolateral to apical direction was slightly higher than that in the opposite direction at concen trations less than 30 muM. [C-14]Ebastine (2 muM) uptake from the apical si de was significantly increased in the presence of an excess of cold CyA, su ggesting that the efflux process mediated by P-gp may be involved in the eb astine uptake by Caco-2 cells. Collectively, these results indicate that eb astine (and presumably M-OH) is transported via P-gp in Caco-2 cells, howev er, the affinity for P-gp is very low. It is unlikely that the secretory tr ansport of ebastine mediated by P-gp will dramatically affect overall intes tinal absorption in vivo because efficient passive diffusion of this drug s hould occur due to its high lipophilicity. However, it may be advantageous for its efficient first-pass metabolism.