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Title: 新規投与形態に基づく肝臓内特定部位への薬物送達システムの開発
Other Titles: Development of drug delivery system based on a new administration route for targeting to the specific region in the liver
Authors: 西田, 孝洋
Authors (alternative): Nishida, Koyo
Issue Date: Aug-2003
Publisher: 日本薬学会 / The Pharmaceutical Society of Japan
Citation: 薬学雑誌 YAKUGAKU ZASSHI, 123 (8): p.681-689 2003
Abstract: 最近の創薬技術は目覚ましく進歩しており,構造活性相関などの多様な情報に基づいて医薬品の候補化合物群を探索し,コンビナトリアルケミストリーの技術で 短期間に合成することが可能となった.また,有用な生物活性を持つ化合物を迅速に選び出すために,スクリーニングロボットが用いられている.さらに,ヒト の遺伝子情報を解読するヒトゲノム解析計画がほぼ完了し,各種生理活性物質や遺伝子治療薬が新規医薬品として期待されている.しかしながら,一般にこのよ うな物質は強力な薬理効果を有するものの生体内への吸収率が低く,速やかに分解を受けてしまうのが現状である.したがって,薬物体内挙動を制御する薬物送 達システム(drug delivery system, DDS)が今まで以上に注目を集めるものと予想され,各種生理活性物質に対する高分子化修飾などのDDS研究が活発に行われている.一方,内視鏡や超音波 診断装置などの高度な医療技術を応用し,生体内の様々な部位へ薬物を投与することが可能となっている.そこで,癌などの病巣部局所へ薬物を選択的に送達で きるDDSを確立するために,肝臓などの腹腔内臓器表面からの吸収を利用した新規な薬物投与形態の開発を試みた.さらに,微視的なレベルで肝臓内薬物動態 を制御できる分子設計の指針について考察した.肝臓は生体内の恒常性維持に重要な役割を果たしており,肝疾患には生命を左右する重篤なものが多いため肝臓 内特定部位へのDDSは非常に意義深い.本総説では,肝臓内特定部位へのDDS開発において,投与形態の側面からアプローチを試み,著者が取り組んできた これまでの研究成果及びその進展,将来性を紹介する. / Development of drug delivery systems 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 advances in life science and biotechnology such as the Human Genome Project. We have tried to develop a new administration route for drug targeting to the liver, since drug administration by the intravenous and oral routes makes it difficult to achieve a local site of action in the liver. Although direct application to the liver surface should result in local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore we analyzed the absorption mechanism of several organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in vivo, employing a cylindrical diffusion cell. Every compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. A specific transport system might not be involved in the absorption process from the liver surface, because the effect of dose and transport inhibitors on the absorption was not recognized. In addition, molecular weight was found to be a determining factor in absorption from the liver surface. The targeting efficacy was considerably enhanced by application to the liver surface, as compared with intravenous administration. Moreover, we have identified important physicochemical and pharmaceutical factors determining the absorption rate of a drug from the liver surface for clinical use. Consequently, drug application to the liver surface could improve availability in the desired site of a new drug such as bioactive compounds and genomic medicines, by combination with appropriate chemical and pharmaceutical formulation modifications.
Keywords: drug targeting / administration route / absorption / organ surface / physicochemical properties
URI: http://hdl.handle.net/10069/6681
ISSN: 00316903
DOI: 10.1248/yakushi.123.681
PubMed ID: 12931664
Relational Links: http://dx.doi.org/10.1248/yakushi.123.681
Rights: Copyright (c) 2003 by the PHARMACEUTICAL SOCIETY OF JAPAN
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/6681

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