Region-dependent disappearance of vinblastine in rat small intestine and characterization of its P-glycoprotein-mediated efflux system

This study was aimed to characterize the absorption behavior of vinblastine (VLB), a well-known substrate of P-glycoprotein (P-gp), from rat small int estine, especially focusing on the regional-dependence of its efflux mediat ed by P-gp. VLB disappeared from duodenal and ileal loops of male Wistar ra ts fairly rapidly (30-60% in 30 min). In contrast, its disappearance from t he jejunal loop was almost negligible and in some rats >100% of the jejunal dose was recovered. The radioactivity derived from [H-3]VLB, which was abs orbed from duodenum and ileum, was detected in the jejunal region. The jeju nal appearance of radioactivity was increased when unlabeled VLB was presen t in the region in advance. The basolateral-to-apical transport of [3H]VLB across Caco-2 cell monolayers was greater when unlabeled VLB was added to t he apical medium than when VLB-free buffer was applied to the apical side. When verapamil or cyclosporin A, potent modulators of P-gp, was added to th e apical medium together with unlabeled VLB, enhanced basolateral-to-apical transport of [H-3]VLB was disappeared. It is suggested that VLB absorption is strongly restricted by P-gp, especially in the jejunal region of the ra t small intestine, and that the secretory transport via intestinal P-gp may be subject to trans-stimulation. Moreover, intravenously administered meth ylprednisolone and intramuscularly administered progesterone significantly enhanced the absorption of VLB, suggesting that parenterally administered P -gp modulators could influence the intestinal absorption of P-gp substrates . (C) 2000 Elsevier Science B.V. All rights reserved.