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。

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.