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

使用大鼠小睾丸激素、可可-2细胞和LLC-PK D21和D2细胞，我们对P-糖蛋白质和相关肠道效应系统的运输特性进行了研究，从而为各种药物的低口腔生物可用性提供了研究。在这一研究中发现的发现是：（1）吸血霉素和阿贝卡辛展示了高度机密的渗透行为，跨越大鼠小意图。这个过程是由多能源依赖的效应系统介导的。P-糖蛋白质是在吸血鬼霉素效应中部分参与的，在作为一个专门的运输机的情况下，它没有在Caco-2细胞膜上表达，有效地运输其他氨基葡萄糖化合物，如良好的arbekacin。（2）甲硫二酮吸收在大鼠intestine中受到P-葡萄糖蛋白质的显著影响，特别是在利比里亚地区。Prednisolone和hydrocortisone是weaker substrates of P-glycoprotein的甲基Prednisolone，建议类固醇激素侧链结构中的轻微差异明显地改变了它们的亲和力 ... More P-glycoprotein。对P-葡萄糖蛋白质在性荷尔蒙等催乳素和睾丸激素的吸收中没有限制。（3）Vinblastine的大鼠体内吸收，一个众所周知的P-糖蛋白质基质，在大鼠二丁二烯和锂中的快速反应比预期的要快。However，从Jejunum吸收葡萄糖几乎是有害的，建议用区域依赖性的术语限制P-糖蛋白质吸收葡萄糖。这样的观察是无法在使用Caco-2细胞的研究中发现的。（4）当对秘密传输、β-乳藻抗微生物与大鼠结肠直肠癌的渗透参数进行正确处理时，它们与人类的口腔生物利用率良好相关。作为一种新的依据，巴坎皮林增加了ampicillin吸收的机理，它被描述为羟基产品，是哪一种形成在表皮中，抑制了β-乳杆菌抗生素的效应系统。（5） [JED 13 JED 1H] Vinblastine， absorbed from duodenum and ileum， is secreted into jejunal lumen much greater when unlabeled Vinblastine is loaded in jejunal loop than when无药物缓冲液被引入。Unlabeled vinblastine also enhances the basolateral-to-apical transport of [イイD13イエD1H] vinblastine mediated by P-glycoprotein across Caco-2 cell monolayers。However，其他P-糖蛋白底物，如多巴胺、文克里斯汀和甲基predni-solone失败，以表现出这样的效果。一个可能的解释是，在表观细胞的物理表面上，表面上相同的物质的存在是刺激P-糖蛋白质介导的传输的关键。Less（低）

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