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Development of Novel Lipophilic Derivatives of DADLE (Leucine Enkephalin Analogue): Intestinal Permeability Characteristics of DADLE Derivatives in Rats

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Abstract

Purpose: The objective of this study is to examine the intestinal permeability of novel lipophilic derivatives of DADLE (Tyr- D-Ala-Gly-Phe-D-Leu), an enkephalin analogue, using isolated rat intestinal membranes.

Methods: The novel lipophilic derivatives of DADLE were synthesized by chemical modification with various fatty acids at the C terminus. The pharmacological activities of these DADLE derivatives were assessed by a hot plate test. The intestinal permeability of these derivatives was estimated by the in vitro Ussing chamber method.

Results: We obtained four different DADLE derivatives including acetyl-DADLE (DADLE-C2), butyryl-DADLE (DADLE-C4), caproyl-DADLE (DADLE-C6), and caprylyl-DADLE (DADLE-C8). All the derivatives of DADLE had at least 75 % of the activity of native DADLE, suggesting that chemical modification of DADLE at the C terminus did not markedly affect its pharmacological activity. These DADLE derivatives were more stable than native DADLE in jejunal and colonic homogenates. A “bell-shaped” profile was observed between the apparent permeability coefficients (Papp) of DADLE derivatives and lipophilicity. In particular, DADLE-C4 had the greatest permeability characteristics across the intestinal membrane of the acyl derivatives studied in this experiment. The permeability of DADLE-C4 across the jejunal membrane was further improved in the presence of puromycin, amastatin, and sodium glycocholate (NaGC), all at a concentration of 0.5 mM.

Conclusions: We suggest that the combination of chemical modification with butyric acid and the application of a protease inhibitor are effective for improving the absorption of DADLE across the intestinal membrane.

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Authors and Affiliations

  1. Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8414, Japan

    Tomomi Uchiyama, Atsushi Kotani, Hiroyuki Tatsumi, Takeshi Kishida, Aya Okamoto, Naoki Okada, Masahiro Murakami, Takuya Fujita, Shozo Muranishi & Akira Yamamoto

  2. Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8414, Japan

    Youichi Fujiwara & Yoshiaki Kiso

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  1. Tomomi Uchiyama
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  2. Atsushi Kotani
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  3. Hiroyuki Tatsumi
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  4. Takeshi Kishida
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  5. Aya Okamoto
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  6. Naoki Okada
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  7. Masahiro Murakami
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  8. Takuya Fujita
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  11. Shozo Muranishi
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  12. Akira Yamamoto
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Correspondence to Akira Yamamoto.

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Uchiyama, T., Kotani, A., Tatsumi, H. et al. Development of Novel Lipophilic Derivatives of DADLE (Leucine Enkephalin Analogue): Intestinal Permeability Characteristics of DADLE Derivatives in Rats. Pharm Res 17, 1461–1467 (2000). https://doi.org/10.1023/A:1007644706286

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