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

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药物递送系统备受关注。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。5-氟尿嘧啶（5-FU）是一种抗癌模型药物，我们利用扩散细胞检测其在大鼠肝表面作用后的肝脏倾向，并指出其作为肝脏靶向药物的可能性。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肝表面直接应用药物靶向方法的可能性。我们采用四氯化碳（CC14）或d -半乳糖胺（GAL）中毒的大鼠作为肝脏疾病模型，利用圆柱形扩散池检测药物在肝脏表面的吸收特性。在肝中毒大鼠中，低分子量药物苯酚磺酞（PSP）作为模型在6 h内从肝表面吸收约90%，与正常大鼠（未处理）相似。虽然CC14组吸收率增加，而GAL组吸收率略有减慢，但临床应用肝表面应用应该没有严重的问题。因此，预计在肝脏疾病状态和肝脏切除时，肝表面吸收率不会明显下降，因此可以将这种给药方法应用于肝脏靶向。

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.