caa a22 4500 477127657 CHVBK 20180405111654.0 cr unu---uuuuu 170330e19970801xx s 000 0 eng 10.1023/A:1012141025938 doi (NATIONALLICENCE)springer-10.1023/A:1012141025938 Metabolism of Azetirelin, a New Thyrotropin-releasing Hormone (TRH) Analogue, by Intestinal Microorganisms [Elektronische Daten] [Isao Sasaki, Takashi Tamura, Tomoko Shibakawa, Takuya Fujita, Masahiro Murakami, Akira Yamamoto, Shozo Muranishi] Purpose. We evaluated the effect of luminal bacterial metabolism on intestinal absorption of azetirelin in rats. In vitro characteristics of bacterial metabolism of azetirelin were also investigated with the goal of overcoming the low stability of the peptidic drug against luminal microorganisms. Methods. Plasma azetirelin levels after oral administration to antibiotic-pretreated rats was examined. In vitro incubation experiments with bacterial suspensions were also performed to clarify the location of azetirelin breakdown activity as well as the effects of oxygen, pH, and various protease inhibitors on drug metabolism. Results. Plasma azetirelin levels were sustained after oral administration to antibiotic-treated rats. Incubation with rat luminal contents demonstrated that azetirelin was metabolized by anaerobic bacteria, which are predominant in the distal intestine. Fecal suspensions from rats, dogs, and humans showed comparable metabolic activity. Azetirelin breakdown in the bacterial suspension was pH-dependent and was inhibited in the presence of bacitracin or puromycin. Conclusions. Bacterial metabolism influences the degree of absorption of azetirelin in the distal intestine. Control of the luminal pH environment may be a practical method for improving the stability of azetirelin against intestinal microorganisms. Plenum Publishing Corporation, 1997 azetirelin nationallicence TRH analogue nationallicence intestinal microorganism nationallicence metabolism nationallicence intestinal absorption nationallicence Sasaki Isao Novel Pharma Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 180 Ozumi, Yaizu-shi, 425, Shizuoka, Japan aut Tamura Takashi Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Shibakawa Tomoko Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Fujita Takuya Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Murakami Masahiro Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Yamamoto Akira Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Muranishi Shozo Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1004-1007 0724-8741 14:8<1004 1997 14 11095 https://doi.org/10.1023/A:1012141025938 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012141025938 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sasaki Isao Novel Pharma Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 180 Ozumi, Yaizu-shi, 425, Shizuoka, Japan aut NATIONALLICENCE 700 1- Tamura Takashi Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 700 1- Shibakawa Tomoko Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 700 1- Fujita Takuya Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 700 1- Murakami Masahiro Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 700 1- Yamamoto Akira Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 700 1- Muranishi Shozo Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1004-1007 0724-8741 14:8<1004 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer