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

随着人类基因组计划等生命科学和生物技术的发展，有望创造出新型药物，因此，开发能够在循环中实现定点递送或长时间滞留的给药系统（DDS）备受关注。我们试图开发一种新的给药途径，使药物靶向到肝脏，因为正常的静脉和口服给药途径难以达到肝脏的局部作用部位。作为开发抗癌药物和基因组肝表面应用配方的基础研究，我们研究了黏性添加剂的黏度对5-氟尿嘧啶（5-FU）从肝表面吸收的影响以及对消除过程的器官特异性抑制。在2004财年，我们将扩散池用于肝表面应用，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的吸收率。此外，我们建议添加15%的PVA可提高肝脏中5-FU的位点特异性。此外，在2005年，我们研究了肝或肾表面应用的probenecid有机阴离子转运抑制剂对苯酚磺酞（PSP）消除过程的器官特异性抑制，旨在开发能够抑制消除过程的新型DDS。在静脉注射probenecide的情况下，未见器官特异性抑制。在肝表面应用时，肝脏和肾脏未发现明显的抑制作用。另一方面，肾表面应用丙苯昔可使PSP的肾脏清除率提高20%。因此，由于肝脏中丙戊酸的量受到抑制，尿中PSP的分泌受到了明显的抑制。

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.