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Metabolism of Azetirelin, a New Thyrotropin-releasing Hormone (TRH) Analogue, by Intestinal Microorganisms

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Abstract

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.

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Author notes

  1. Takashi Tamura

    Present address: Pharmaceutics Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89 Kawashima, Yodogawa-ku, Osaka, 532, Japan

Authors and Affiliations

  1. Novel Pharma Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 180 Ozumi, Yaizu-shi, Shizuoka, 425, Japan

    Isao Sasaki

  2. Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607, Japan

    Takashi Tamura, Tomoko Shibakawa, Takuya Fujita, Masahiro Murakami, Akira Yamamoto & Shozo Muranishi

Authors
  1. Isao Sasaki
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  2. Takashi Tamura
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  3. Tomoko Shibakawa
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  4. Takuya Fujita
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  5. Masahiro Murakami
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  6. Akira Yamamoto
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  7. Shozo Muranishi
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Sasaki, I., Tamura, T., Shibakawa, T. et al. Metabolism of Azetirelin, a New Thyrotropin-releasing Hormone (TRH) Analogue, by Intestinal Microorganisms. Pharm Res 14, 1004–1007 (1997). https://doi.org/10.1023/A:1012141025938

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  • DOI: https://doi.org/10.1023/A:1012141025938

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