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大学・研究所にある論文を検索できる 「ラットを用いた薬物の消化管吸収におけるシトクロムP450 3A、P-糖蛋白質及び乳癌耐性蛋白質の寄与を評価する方法に関する研究」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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ラットを用いた薬物の消化管吸収におけるシトクロムP450 3A、P-糖蛋白質及び乳癌耐性蛋白質の寄与を評価する方法に関する研究

鈴木 敬 Kei Suzuki 東京理科大学 DOI:info:doi/10.20604/00003638

2021.06.09

概要

新薬開発において、低分子薬の多くが経口剤として開発される。経口投与された医薬品が全身循環に到達するためには、消化管内で溶解した後に、消化管上皮細胞膜を透過し、消化管及び肝臓での代謝を免れる必要がある。肝臓は薬物代謝酵素の発現量が高く、解毒臓器として知られているが、消化管上皮細胞にも同様に、薬物代謝酵素であるシトクロムP450(CYP)3A、並びに薬物トランスポーターであるP-糖蛋白質(P-gp)及び乳癌耐性蛋白質(BCRP)等が発現しており、これらが生体防御機構として働くことにより薬物の消化管吸収が制限され、生物学的利用率が低下することがある。

非臨床薬物動態試験において、ラットは最も汎用される動物種の一つである。ヒト及びラットに経口投与したときの生物学的利用率には種差があることが報告されているが、その主な原因は肝代謝に起因したものであり、消化管吸収率のラット•ヒト間種差は小さいことが報告されている。このため、ラットにおいて消化管吸収率の高い化合物を創製することは、ヒトにおいても高い消化管吸収性を示す確率が高く、開発成功確率を高めると考えられる。しかしながら、創薬初期段階においては、ラットにおいて新薬候補化合物の消化管吸収性が低いという課題に直面するケースがしばしば見られる。消化管吸収率が低くなる原因としては、消化管内における低溶解性等の物性的要因に加えて、低膜透過性、CYP3A等による消化管代謝、並びにP-gp及びBcrpによる消化管管腔への排泄等の生物学的要因が挙げられる。様々な原因が考えられる中で、新薬候補化合物の薬物動態学的プロファイルを最適化するためには、消化管吸収率が低い原因を究明する必要があると考えられる。

本論文は三章から構成され、各章では、ラット消化管での薬物吸収過程におけるCYP3A4.P-gp及びBcrpの寄与を評価する方法を構築することを目的として、それぞれ阻害薬としてベルガモチン、エラクリダル及びノボビオシンを用いて検討を行った。

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