著者

高倉 喜信 藤田 卓也 橋田 充 瀬崎 仁

出版者

日本DDS学会

雑誌

Drug Delivery System (ISSN:09135006)

巻号頁・発行日

vol.3, no.3, pp.405-409, 1988-10-01 (Released:2009-02-23)

参考文献数

12

被引用文献数

1 1

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The disposition and tumor localization of model macromolecules with the same molecular weight but different electric charge were studied in sarcoma 180 bearing mice. Dextran (T-70) with molecular weight of 70, 000, cationic DEAE-dextran (T-70), anionic CM-dextran (T-70), bovine serum albumin(BSA), and cationized BSA (cBSA)were injected intravenously and their tissue distribution was determined by radioactivity counting. The cationic macromolecules were rapidly cleared from plasma and accumulated in the liver, and spleen or excreted into urine, while tumor levels remained low. On the contrary, anionic macromolecules were retained in the plasma for a long time and slowly accumulated to the tumor. The present study revealed that macromolecules having an anionic charge are advantageous for tumor targeting.

著者

佐々木 功 藤田 卓也 村上 正裕 山本 昌 中村 英次 今崎 一 村西 昌三

出版者

公益社団法人日本薬学会

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.17, no.9, pp.1256-1261, 1994-09-15

被引用文献数

13 18

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Absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, from the gastrointestinal (GI) tract was evaluated. The bioavailability of this compound after oral administration was considerably poor in rats. Studies were undertaken to elucidate the mechanisms for this low oral bioavailability of azetirelin. The plasma azetirelin levels following intravenous and hepatoportal vein injection were virtually identical over the dose range of 0.02-0.1 mg/kg, indicating a minor contribution of the hepatic first-pass metabolism of this drug. Azetirelin was stable against peptide hydrolases both in luminal fluid and intestinal mucosal homogenates, whereas its degradation occurred when incubated with cecal contents under an anaerobic condition. In addition, complete degradation of azetirelin during the GI transit was disclosed by analyzing the fecal sample collected after oral administration of [^<14>C] azetirelin. These results suggested that gut bacteria may be responsible for the hydrolysis of azetirelin in the GI tract. The low intestinal permeability of azetirelin was revealed by a modified everted gut experiment in various segments of the rat intestine. The poor membrane transport characteristics of azetirelin may be due to its high hydrophilicity. From these results, it was suggested that the insufficient oral bioavailability of azetirelin may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity, and also to the degradation of the peptide by intestinal microflora.