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

P-糖蛋白和相关转运蛋白的转运特性导致各种药物口服生物利用度低的研究。

基本信息

批准号：
10672091
负责人：
SAITOH Hiroshi
金额：
$ 1.73万
依托单位：
Health Sciences University of Hokkaido
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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

使用大鼠小肠,Caco-2细胞,LLC-PKィイD21ィエD2细胞,我们调查运输22的特点和相关的肠道排出系统贡献各种药物的口服生物利用度低。本研究发现：(1)万古霉素和阿贝卡星在大鼠小肠中表现出高度分泌导向的渗透方式。该过程是由多个能量依赖的外排系统介导的。p -糖蛋白部分参与万古霉素的外排，而一种特殊的转运蛋白，不在Caco-2细胞膜上表达，有效地运输其他氨基糖苷和阿贝卡星。(2) p -糖蛋白显著影响甲泼尼龙在大鼠肠道的吸收，特别是在回肠区。与甲基强的松相比，强的松和氢化可的松是p -糖蛋白较弱的底物，这表明类固醇激素侧链结构的微小差异会显著改变它们对p -糖蛋白的亲和力。p -糖蛋白对黄体酮和睾酮等性激素的吸收没有限制。(3)长春碱是一种已知的p糖蛋白底物，其在大鼠十二指肠和回肠中的吸收比预期的要快。然而，空肠对长春碱的吸收几乎可以忽略不计，提示p -糖蛋白以区域依赖的方式限制长春碱的吸收。在使用Caco-2细胞的研究中无法获得这种观察结果。(4) β-内酰胺类抗生素经分泌转运校正后，其在大鼠空肠中的渗透参数与其在人体内的口服生物利用度密切相关。作为对苯氨苄青霉素增加氨苄青霉素吸收机制的新认识，表明在上皮内形成的水解产物抑制了β-内酰胺类抗生素的外排系统。(5)从十二指肠和回肠吸收的长春碱，在空肠袢中装载未标记的长春碱时，其分泌到空肠腔的量远高于引入无药物缓冲液时。未标记的长春花碱还增强了p -糖蛋白介导的[γ γ γ γ γ γ γ γ γ γ γ]长春花碱在Caco-2细胞单层上的基底侧到根尖运输。然而，其他p糖蛋白底物如阿霉素、长春新碱和甲基泼尼-索龙则没有这种作用。一种可能的解释是，在上皮细胞的顶端表面存在相同的底物是刺激p -糖蛋白介导的转运的关键。少