| Development of novel lipophilic derivatives of DADLE (leucine enkephalin analogue): intestinal permeability characateristics of DADLE derivatives in rats. | |
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MedLine Citation:
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PMID: 11303954 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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T Uchiyama; A Kotani; H Tatsumi; T Kishida; A Okamoto; N Okada; M Murakami; T Fujita; Y Fujiwara; Y Kiso; S Muranishi; A Yamamoto |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Pharmaceutical research Volume: 17 ISSN: 0724-8741 ISO Abbreviation: Pharm. Res. Publication Date: 2000 Dec |
Date Detail:
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Created Date: 2001-04-16 Completed Date: 2001-07-12 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: United States |
Other Details:
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Languages: eng Pagination: 1461-7 Citation Subset: IM |
Affiliation:
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Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chemistry, Physical Colon / metabolism Enkephalin, Leucine / analogs & derivatives*, pharmacokinetics, pharmacology* Enkephalin, Leucine-2-Alanine / chemistry, pharmacokinetics, pharmacology* Half-Life Intestinal Absorption / physiology Intestines / metabolism Jejunum / metabolism Lipids / chemistry Membranes / metabolism Physicochemical Phenomena Rats |
| Chemical | |
Reg. No./Substance:
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0/Lipids; 58822-25-6/Enkephalin, Leucine; 63631-40-3/Enkephalin, Leucine-2-Alanine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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