著者

吉川 広之 村西 昌三

出版者

日本DDS学会

雑誌

Drug Delivery System (ISSN:09135006)

巻号頁・発行日

vol.6, no.3, pp.159-164, 1991-05-10 (Released:2009-02-23)

参考文献数

26

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Blood is known to be the main transport route of most drugs because of the much greater flow rate of the blood stream than that of the lymphatics. The lymphatic transport of drugs, however, is noteworthy, because the lymphatic route is important for many chemicals ; namely as an essential route for nutrient lipids and a route to avoid the first pass effect of the liver for drugs which are absorbed from the gastrointestinal tract and the necessity to deliver anticancer agents into the lymphatic system of patients suffering from the cancer. It follows that in tumor metastasis, the lymphatic pathway is a major route and a lymphotropic transport of antitumor drugs is to be of great significance for cancer chemotherapy. In this paper, fundamentals of lymphatic transport of chemicals, development of lymphotropic drug delivery systems and their application to therapy are described.

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.