大腸粘膜のバリアー能について、透過し得る分子サイズの小腸粘膜との差を明らかにするため、水溶性化合物で分子量の異なるpolyethylene glycol(PEG)300,600及び1000を用いて、in situループ法によりラット小腸及び大腸からの吸収を検討した。用いたPEGはそれぞれ分子量300,600及び1000を中心に、重合度の異なる各種分子量のPEGの混合物である。その結果、小腸では分子量600付近まで吸収が認められるのに対して、大腸では分子量300以上では吸収は困難であった。これらのPEGについては細胞間隙を通るいわゆる経細胞側路が考えられるが、両部位での透過可能な分子量すなわち分子サイズの差は細胞間隙の大きさの違いに基づくものと思われる。この点については電気生理学的解析によっても裏付けられた。また、細胞間隙の帯電状態の違いも示唆されたが、細胞間隙に作用する吸収促進剤EDTAの作用はその帯電状態への影響も含むことが明らかとなった。一方、経細胞路の透過性は薬物の親油性に左右されるが、小腸と大腸では吸収の親油性との関係に違いが見られた。3種のアシルサリチル酸を用いて吸収実験を行った結果、小腸部の方が大腸部より極めて吸収がよく、大腸の中では結腸の方が直腸より吸収が良好であった。これは大腸よりも小腸、特に小腸上部では吸収表面積が大きいことが寄与していると考えられる。また、どの部位でもアシル鎖が長くなるに従って吸収が良好になっているが、小腸部では親油性が増しても、吸収が頭打ちになった。そこで、親油性の異なる2種類の薬物acetaminophen とindomethacinの吸収を評価したところ、高親油性薬物の場合には小腸と大腸で吸収速度に差がなくなることが分かった。これらの現象は粘膜表面近傍に存在する非攪拌水層の抵抗の部位差で説明することができた。
- 著者
- 山尾 忠直 中上 博秋 古濱 和久 小野寺 威 黒崎 勇二 中山 太二 木村 聰城郎
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.17, no.5, pp.691-695, 1994-05-15 (Released:2008-04-10)
- 参考文献数
- 16
- 被引用文献数
- 6 6
The pharmacokinetics of tolbutamide (TB) following intravenous and oral administration was compared between normal rats and rats with experimentally-induced obstructive jaundice (OJ). The plasma concentration-time curve of i.v. administered TB was lower in rats with OJ, in comparison with normal rats. The result of the pharmacokinetic analysis showed no change in the elimination rate constant, but a significant increase in the volume of distribution in the OJ state. The increase in the volume of distribution of TB could be explained by the decreased protein binding in plasma. In the case of oral administration, the elevation of the plasma concentration was slow and the plasma concentration profile was remarkably low in rats with OJ. The rate of TB disappearance from the small-intestinal lumen was delayed in the OJ state, and its marked accumulation in the tissues of the small intestine and the liver was observed. This retarded uptake by the small-intestinal mucosa and subsequent pre-systemic accumulation might, at least in part, be the reason for the slow appearance in the systemic plasma in the OJ state.
1 0 0 0 OA 感染症とDDS
- 著者
- 木村 聰城郎
- 出版者
- 日本DDS学会
- 雑誌
- Drug Delivery System (ISSN:09135006)
- 巻号頁・発行日
- vol.15, no.3, pp.160-164, 2000-05-10 (Released:2008-12-26)
- 参考文献数
- 12
A number of antimicrobial agents have been developed since penicillin was discovered. In spite of the strong antimicrobial activity, some of them are difficult to be used clinically due to their various side effects including the organ toxicity. On the other hand, some of them are not suitable for oral administration because of their poor absorbability. To overcome these problems, DDS technology has been applied. Some poorly absorbable drugs became to be used as the oral dosage form by converting to the well-absorbable prodrugs. Lipid-dispersed formulations, such as liposomes and lipid-nanospheres, of amphotericin B could make the antifungal drug less toxic and more effective. Recently, extensive studies are conducted to treat or protect against the virus infections. Oral vaccine delivery is one of the most attractive objectives. The use of the particulate dosage form has been investigated to deliver the vaccine to M cells. However, the most suitable properties of the carrier particles for the extensive binding to M cells and the sequential uptake remain to be clarified. To protect against influenza virus infection, the nasal applications of influenza vaccine were examined. The high protection against the viral challenge by the administration of influenza vaccine with sodium polystyrene sulfonate resin or CT 112 K, a mutant of cholera toxin, as the adjuvant was shown by the experiments in mice. The plasmid DNA could also protect against in influenza virus infection in mice while the method of effective introduction of the plasmid DNA to mucosal cells should be developed. The optimal DDS technology will lead the success of these novel approaches.