This study was aimed to characterize the absorption behavior of vinblastine (VLB), a well-known substrate of P-glycoprotein (P-gp), from rat small intestine, especially focusing on the regional-dependence of its efflux mediated by P-gp. VLB disappeared from duodenal and ileal loops of male Wistar rats fairly rapidly (30-60% in 30 min). In contrast, its disappearance from the 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 absorbed from duodenum and ileum, was detected in the jejunal region. The jejunal appearance of radioactivity was increased when unlabeled VLB was present 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 the 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 the 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 rat small intestine, and that the secretory transport via intestinal P-gp may be subject to trans-stimulation. Moreover, intravenously administered methylprednisolone 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.
