|Budget Amount *help
¥2,700,000 (Direct Cost : ¥2,700,000)
Fiscal Year 1999 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1998 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Using rat small intestine, Caco-2 cells, and LLC-PKィイD21ィエD2 cells, we investigated transport characteristics of P-glycoprotein and related intestinal efflux system contributing the low oral bioavailability of various drugs. The findings obtained in this study were as follows:
(1) Vancomycin and arbekacin exhibit highly secretory-oriented permeation manner across rat small intestine. The process is mediated by plural energy-dependent efflux systems. P-Glycoprotein is in part involved in vancomycin efflux, whereas a specialized transporter, which is not expressed on Caco-2 cell membrane, efficiently transports other aminoglycosides as well as arbekacin.
(2) Methyiprednisolone absorption is markedly affected by P-glycoprotein in the rat intestine, especially in the ileal region. Prednisolone and hydrocortisone are weaker substrates of P-glycoprotein than methylprednisolone, suggesting that slight differences in side chain structure of steroid hormones are significantly alter their affinity
to P-glycoprotein. There is no restriction due to P-glycoprotein in the absorption of sex hormones like progesterone and testosterone.
(3) Rat intestinal absorption of vinblastine, a well-known substrate of P-glycoprotein, is rapid in rat duodenum and ileum than expected. However, vinblastine absorption from jejunum is almost negligible, suggesting that P-glycoprotein restrict vinblastine absorption in regional-dependent manner. Such observation cannot be obtained in the study using Caco-2 cells.
(4) When corrected for the secretory transport, permeation parameters of β-lactam antibiotics across rat jejunum are well correlated with their oral bioavailability in human. As a new understanding on the mechanism by which bacampicillin increase ampicillin absorption, it is indicated that a hydrolysis product, which is formed in the epithelium, inhibits the efflux system for β-lactam antibiotics.
(5) [ィイD13ィエD1H] Vinblastine, absorbed from duodenum and ileum, is secreted into jejunal lumen much greater when unlabeled vinblastine is loaded in jejunal loop than when drug-free buffer was introduced. Unlabeled vinblastine also enhances the basolateral-to-apical transport of [ィイD13ィエD1H] vinblastine mediated by P-glycoprotein across Caco-2 cell monolayers. However, other P-glycoprotein substrates like doxorubicin, vincristine, and methylpredni-solone fail to exhibit such effect. A likely explanation is that the presence of the same substrate at the apical surface of epithelial cells is a key to stimulate P-glycoprotein-mediated transport. Less