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Titolo:
Development of novel lipophilic derivatives of DADLE (Leucine enkephalin analogue): Intestinal permeability characteristics of DADLE derivatives in rats
Autore:
Uchiyama, T; Kotani, A; Tatsumi, H; Kishida, T; Okamoto, A; Okada, N; Murakami, M; Fujita, T; Fujiwara, Y; Kiso, Y; Muranishi, S; Yamamoto, A;
Indirizzi:
Kyoto Pharmaceut Univ, Dept Biopharmaceut, Yamashina Ku, Kyoto 6078414, Japan Kyoto Pharmaceut Univ Kyoto Japan 6078414 shina Ku, Kyoto 6078414, Japan Kyoto Pharmaceut Univ, Dept Med Chem, Yamashina Ku, Kyoto 6078414, Japan Kyoto Pharmaceut Univ Kyoto Japan 6078414 shina Ku, Kyoto 6078414, Japan
Titolo Testata:
PHARMACEUTICAL RESEARCH
fascicolo: 12, volume: 17, anno: 2000,
pagine: 1461 - 1467
SICI:
0724-8741(200012)17:12<1461:DONLDO>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
THYROTROPIN-RELEASING-HORMONE; CHEMICAL MODIFICATION; FATTY-ACIDS; ABSORPTION ENHANCERS; PROTEASE INHIBITORS; CACO-2 MONOLAYERS; TRANSPORT-SYSTEM; ALBINO RABBIT; LAURIC ACID; IMPROVEMENT;
Keywords:
drug absorption; peptide delivery; enkephalin; absorption enhancement; chemical modification; protease inhibitor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Yamamoto, A Kyoto Pharmaceut Univ, Dept Biopharmaceut, Yamashina Ku, Kyoto6078414, Japan Kyoto Pharmaceut Univ Kyoto Japan 6078414 oto 6078414, Japan
Citazione:
T. Uchiyama et al., "Development of novel lipophilic derivatives of DADLE (Leucine enkephalin analogue): Intestinal permeability characteristics of DADLE derivatives in rats", PHARM RES, 17(12), 2000, pp. 1461-1467

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). anenkephalin 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 thein 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. Inparticular, 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 withbutyric acid and the application of a protease inhibitor are effective forImproving the absorption of DADLE across the intestinal membrane.

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Documento generato il 14/07/20 alle ore 10:10:18