Investigation on the Transport Characteristics of P-Glycoprotein and Related Transporters Contributing Low Oral Bioavailability of Various Drugs.

Using rat small intestine, Caco-2 cells, and LLC-PK -2 cells，我们投资传输characteristics of P-glycoprotein and相关的intestinal efflux系统contributing the low oral bioavailability of various drugs. the findings obtained in this study were以下：(1)Vancomycin and arbekacin exhibit highly secretory-oriented permeation manner acrossrat small intestine. The process is mediated by plural energy-dependent efflux systems.P-Glycoprotein is in part involved in vancomycin efflux, whereas a specialized transporterCaco-2 cell membrane，(2) Methyiprednisolone absorption efficiently transports其他aminoglycosides as arbekacin.(2) Methyiprednisolone absorptionis markedly affected by P-glycoprotein in the rat intestine，especially in the ileal region. Prednisolone and hydrocortisone are weaker substrates ofP-glycoprotein than methylprednisolone，suggesting that slight differences in side chain structure of steroid hormones are significantlyalter their affinity…More to P-glycoprotein. There is no restriction due to P-glycoprotein the absorption ofsex hormones like progesterone and testosterone.(3) Rat intestinal absorption of vinblastine，a well-known substrate of P-glycoprotein，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. Suchobservation cannot be obtained in the study using Caco-2 cells.(4) When corrected for the secretorytransport,permeation parameters of β-lactam antibiotics across rat jejunum are correlated with their oralbioavailability in human. As a new understanding on the mechanism by which bacampicillin increaseampicillin absorption， it is indicated that a hydrolysis产品，which is formed in the epithelium，inhibits the efflux system for β-lactam antibiotics.(5) [D13 D1H] Vinblastine，absorbed from duodenum and ileum，secreted into jejunal lumen much greater when unlabeled vinblastine is loaded in jejunal loopthan when drug-free buffer was introduced. Unlabeled vinblastine also enhances thebasolateral-to-apical transport of [D13 D1H] vinblastine mediated by P-glycoprotein across cco -2cell monolayers. However, other P-glycoprotein substrates like doxorubicin, vincristine，methylpredni-solone fail to exhibit such effect. A likely explanation is that the presence ofsame substrate at the apical surface of epithelial cells is a key to stimulateP-glycoprotein-mediated transport. Less

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 … More 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