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Development of the drug delivery system for brain and cancer using the inhibitory effect of some drugs on the active efflux : Application of physiological pharmacokinetics.

利用某些药物对主动外排的抑制作用开发脑和癌症药物递送系统：生理药代动力学的应用。

基本信息

批准号：
04557106
负责人：
SUGIYAMA Yuichi
金额：
$ 8.32万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

[1] Transport mechanism of peptides : Using a monoclonal antibody to transferrin as a model polypeptide, the transport mechanism for piptide in blood-brain barrier (BBB) was examined. The permeability of this antibody for blood-brain barrier was evaluated with in situ brain perfusion system, in vitro isolated and cultured bovine brain endotherial cells. As a result, the existence of receptor-mediated endocytosis pathway was suggested to be existed. By complex formation of this antibody and the polypeptide, it may possibly be improved that the net transfer of the polypeptide into the brain across the BBB.[2] Transport mechanism for hydrophilic drugs : Using quinolone derivatives (NQs) and anti-AIDS drugs (azidothymidine and dideoxyinosine) as model drugs, the mechanism for the disposition in the central nervous system (CNS) were examined with in vivo and in vitro experimental systems. For anti-AIDS drugs, the uptake from blood to brain was suggested to be active transport. In vitro uptake studies using isolated choroid plexus revealed that NQs was pumped out from cerebrospinal fluid to the circulating blood by an active organic anion transport system which is identical with that for benzylpenicillin. In addition, not only anti-AIDS drugs but NQs are also taken up by choroid plexus in a active transport manner.[3] Prediction of the disposition with physiological pharmacokinetics : Analysis based on the distributed model in which the ligand exchange between the plasma, brain, and cerebrospinal fluid is considered revealed that the CNS to plasma unbound concentration ratio of NQs can be predicted using the determined clearance values, which were determined with several experimental systems described above, for the transport across the barriers.

[1]肽的转运机制：以转铁蛋白单克隆抗体为模型多肽，研究了piptide在血脑屏障（BBB）中的转运机制。用原位脑灌流系统和体外分离培养的牛脑内皮细胞检测该抗体对血脑屏障的通透性。结果表明，存在受体介导的内吞途径。通过该抗体和多肽的复合物形成，可能改善多肽穿过BBB净转移到脑中。[2]亲水性药物的转运机制：以喹诺酮类药物和抗艾滋病药物（叠氮胸苷和双脱氧肌苷）为模型药物，通过体内外实验系统研究了亲水性药物在中枢神经系统（CNS）中的分布机制。对于抗艾滋病药物，从血液到脑的摄取被认为是主动转运。离体脉络丛的体外摄取研究表明，NQs是通过一种与青霉素相同的活性有机阴离子转运系统从脑脊液中泵入循环血液的。此外，脉络丛不仅摄取抗艾滋病药物，而且也以主动转运的方式摄取NQs。[3]预测生理药代动力学的处置：基于分布式模型（其中考虑了血浆、脑和脑脊液之间的配体交换）的分析显示，可以使用测定的清除率值（使用上述几种实验系统测定）预测NQ的CNS与血浆未结合浓度比，用于跨屏障转运。