Development of liver surface application form of anticancer drugs and genome medicine aiming to specific therapy of the diseased region in the organ

开发抗癌药物和基因组医学的肝表面应用形式，针对器官病变部位进行特异性治疗

• 批准号: 16590029
• 负责人: NISHIDA Koyo
• 金额: $ 2.37万
• 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: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590029/
• 关键词: liver; anticancer drug; drug interaction; liver disease; intraperitoneal administration; pharmacokinetics; 粘性; 吸収速度

Development of drug delivery system (DDS) 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 a basic research of developing liver surface application formulation for anticancer drugs and genome, we studied the effect of viscosity of viscous additives on the absorption of 5-fluorouracil (5-FU) from the liver surface and the organ-specific inhibition of elimination process. In the fiscal year of 2004, we employed the diffusion cell for liver surface application and clarified that the absorption rate of 5-FU was decreased by addition of viscous additives (polyvinyl alcohol PVA, sodium carboxymethylcellulose). Moreover, we suggested that site specificity of 5-FU in the liver was improved by addition of PVA 15%. Furthermore, in 2005, we examined the organ-specific inhibition of elimination process of phenolsulfonphthalein (PSP) by probenecid organic anion transport inhibitor by liver or kidney surface application, aiming to develop the new DDS capable of inhibition of elimination process. In the case of i.v. probenecid administration, organ-specific inhibition was not seen. In the case of liver surface application, significant inhibition effect was not recognized in the liver and kidney. On the other hand, kidney surface application of probenecid resulted in 20% of renal clearance of PSP. Accordingly, significant inhibition of urinary secretion of PSP was implied, due to suppression of probenecid amount in the liver.

随着生命科学和生物技术(如人类基因组计划)的发展，药物传递系统(DDS)的开发已经引起了人们的关注，因为新型药物有望随着生命科学和生物技术(如人类基因组计划)的进步而创造出来。我们试图开发一种新的肝靶向给药途径，因为正常的静脉和口服给药途径很难在肝脏实现局部作用部位。作为开发抗癌药物和基因组肝脏表面应用制剂的基础研究，我们研究了粘性添加剂粘度对5-氟尿嘧啶(5-FU)从肝脏表面吸收的影响以及对消除过程的器官特异性抑制。在2004财政年度，我们使用扩散池进行肝脏表面应用，并澄清了添加粘性添加剂(聚乙烯醇PVA、羧甲基纤维素钠)会降低5-FU的吸收速率。此外，我们认为添加15%的PVA可以提高5-FU在肝脏中的位置特异性。此外，我们在2005年考察了丙磺舒有机阴离子转运抑制剂通过肝脏或肾脏表面应用对酚红(PSP)消除过程的器官特异性抑制作用，旨在开发能够抑制消除过程的新的DDS。在静脉注射的情况下。丙磺舒给药后，未见器官特异性抑制。在肝脏表面应用的情况下，在肝脏和肾脏没有发现明显的抑制作用。另一方面，肾表面应用丙磺舒可使PSP的肾脏清除率达到20%。因此，由于丙磺舒在肝脏中的量被抑制，因此PSP的尿液分泌明显受到抑制。

项目成果

Absorption characteristics of model compounds from the small intestinal serosal surface and a comparison with other organ surfaces

模型化合物从小肠浆膜表面的吸收特性及与其他器官表面的比较

• 发表时间: 2005
• 期刊: Journal of Pharmacy and Pharmacology 57・8
• 作者: T.Ichibangase;et al.;Koyo Nishida
• 通讯作者: Koyo Nishida

Absorption of phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration

以酚磺酞在大鼠肠系膜表面吸收为模型，确定腹腔给药后的药物吸收途径

• 发表时间: 2004
• 期刊: Journal of Pharmacy and Pharmacology 56・5
• 作者: N.Kuroda;et al.;Keisuke Ueda;Masayuki Yoshikawa et al.;Koyo Nishida
• 通讯作者: Koyo Nishida

Delivery advantage to the unilateral kidney by direct drug application to the kidney surface in rats and pharmacokinetic verification based on a physiological model

• DOI: 10.1080/10611860500159097
• 发表时间: 2005-05
• 期刊: Journal of Drug Targeting
• 影响因子: 4.5
• 作者: K. Nishida;Manabu Kamenosono;A. Kuma;S. Fumoto;T. Mukai;M. Nakashima;H. Sasaki;J. Nakamura

Regional delivery of model compounds and 5-fluorouracil to the liver by their application to the liver surface in rats : Its implication for clinical use

通过将模型化合物和 5-氟尿嘧啶应用到大鼠肝脏表面来将模型化合物和 5-氟尿嘧啶区域递送至肝脏：其临床应用的意义

• 发表时间: 2005
• 期刊: Pharmaceutical Research 22・8
• 作者: Yokoo K;Watanabe H;Hamada A;et al.;Aiko Ebisawa;Koyo Nishida
• 通讯作者: Koyo Nishida

Absorption characteristics of compounds with different molecular weights after application to the unilateral kidney surface in rats

不同分子量化合物涂敷于大鼠单侧肾表面后的吸收特性

• 发表时间: 2004
• 期刊: European Journal of Pharmaceutics and Biopharmaceutics 57・3
• 作者: K.Ohyama;et al.;Masayuki Yoshikawa et al.;Hiromasa Kurosaki;Takashi Katsu;Koyo Nishida
• 通讯作者: Koyo Nishida