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Targeting of anticancer drugs and genome medicine by utilizing absorption from the liver surface

利用肝脏表面的吸收靶向抗癌药物和基因组医学

基本信息

批准号：
14572033
负责人：
NISHIDA Koyo
金额：
$ 2.24万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572033/
关键词：
liver anticancer drug liver disease intraperitoneal administration absorption rate oharmacokinetics 抗癌剤

项目摘要

Development of drug delivery system to achieve site-specific delivery or prolonged retention in the circulation has attracted attention, because new types of drugs are expected to be created with advance in life science and biotechnology such as human genome project. We have tried to develop a new administration route for drug targeting to the liver, since normal drug administration by intravenous and oral route have difficulty in achieving a local site of action in the liver. As an anticancer model drug 5-fluorouracil (5-FU), we examined its hepatic disposition after application to the rat liver surface by employing a diffusion cell, and indicated the possibility for liver targeting. In addition, we suggested the novel application route to the other organ surfaces for genome medicine. Furthermore, we have examined the influence of liver disease on drug absorption from the liver surface membrane regarded as the first barrier for drug targeting to the liver. The main purpose of this study is to examine the possibility of direct liver surface application for drug targeting method. We employed rats intoxicated with carbon tetrachloride (CC14) or D-galactosamine (GAL) as the liver disease model, and examined drug absorption characteristics after application to the liver surface, by utilizing a cylindrical diffusion cell. In the liver-intoxicated rats, about 90 % of a low molecular weight drug phenolsulfonphthalein (PSP) as a model was absorbed from the liver surface in 6 h, similar to the normal rats (no treatment). Although the absorption rate was increased in the CC14 group whereas slightly retarded absorption was observed in GAL group, there should be no serious problem for clinical use of liver surface application. Consequently, it is expected that no marked decline in the absorption rate from liver surface in liver disease state and liver resection, leading to apply this administration method for liver targeting.

随着生命科学和生物技术的发展，如人类基因组计划，新型药物有望产生，因此开发药物递送系统以实现位点特异性递送或延长在循环中的保留已引起关注。我们已经尝试开发一种新的药物靶向肝脏的给药途径，因为通过静脉内和口服途径的正常药物给药难以在肝脏中实现局部作用位点。作为一种抗癌模型药物5-氟尿嘧啶（5-FU），我们研究了它的肝脏处置后，应用到大鼠肝脏表面的扩散池，并指出肝靶向的可能性。此外，我们还提出了基因组药物在其他器官表面应用的新途径。此外，我们还研究了肝脏疾病对药物从肝表面膜吸收的影响，肝表面膜被认为是药物靶向肝脏的第一道屏障。本研究的主要目的是探讨直接应用于肝脏表面的药物靶向方法的可能性。我们采用四氯化碳（CC 14）或D-氨基半乳糖（GAL）中毒的大鼠作为肝脏疾病模型，并利用圆柱形扩散池检测药物应用于肝脏表面后的吸收特性。在肝中毒大鼠中，作为模型的低分子量药物酚磺酞（PSP）在6 h内从肝表面吸收约90%，与正常大鼠（未处理）相似。虽然CC 14组的吸收率增加，而GAL组的吸收略有延迟，但肝脏表面应用的临床使用应该没有严重问题。因此，预期在肝病状态和肝切除术中肝脏表面的吸收率不会显著下降，从而导致将该给药方法应用于肝靶向。