A serotonin antagonist azasetron, which is relatively hydrophilic and cationic compound, has been shown to exhibit a relatively high and a dose-dependent increase of intestinal absorbability. In the present study, the significant contribution of a specific secretory mechanism to the nonlinear intestinal absorption of azasetron and other drugs was studied. The initial uptake rate of azasetron by Caco-2 cells was saturable and temperature-dependent, demonstrating a participation of a carrier-mediated uptake process. Net transport of [¹⁴C]azasetron from basolateral-to-apical-side across Caco-2 cells was greater than that from apical to basolateral side. When 0.5 mM unlabeled azasetron was included in the apical side medium, apical-to-basolateral transport of [¹⁴C]azasetron was enhanced, whereas basolateral-to-apical transport was decreased. However, when higher concentrations of unlabeled azasetron were added, a decreased apical-to-basolateral and an increased basolateral-to-apical transport of [¹⁴C]azasetron were observed.
Furthermore, first-order intestinal absorption rate constants of azasetron, which were evaluated by Doluisio's technique in rats, exhibited a complicated nonlinear feature. Namely, the rate constant was increased with increasing concentration of azasetron from 0.01 to 10 mM, whereas the value was decreased at higher concentrations up to 60 mM. These results may demonstrate that an intestinal absorption of azasetron includes two nonlinear processes, including carrier-mediated uptake and specific secretory mechanisms. Interestingly, since cyclosporin A inhibited secretory process of azasetron in Caco-2 cells, P-glycoprotein may be involved as the secretory mechanism. Similar nonlinear increase of intestinal absorption was observed in cyclosporin A after intra-ileal administration in rats. In addition, intestinal absorption of cyclosporin A was increased with a coadministration of P-glycoprotein inhibitor.
These results demonstrate that the specific intestinal secretory mechanism is a significant factor, resulting in nonlinear increase of oral bioavailability.