Development of novel lipophilic derivatives of DADLE (Leucine enkephalin analogue): Intestinal permeability characteristics of DADLE derivatives in rats

Citation
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
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACEUTICAL RESEARCH
ISSN journal
0724-8741 → ACNP
Volume
17
Issue
12
Year of publication
2000
Pages
1461 - 1467
Database
ISI
SICI code
0724-8741(200012)17:12<1461:DONLDO>2.0.ZU;2-9
Abstract
Purpose: The objective of this study is to examine the intestinal permeabil ity 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 chem ical modification with various fatty acids at the C terminus. The pharmacol ogical activities of these DADLE derivatives were assessed by a hot plate t est. The intestinal permeability of these derivatives was estimated by the in vitro Ussing chamber method. Results: We obtained four different DADLE derivatives including acetyl-DADL E (DADLE-C2), butyryl-DADLE (DADLE-C4). caproyl-DADLE (DADLE-C6), and capry lyl-DADLE (DADLE-C8). All the derivatives of DADLE had at least 75 % of the activity of native DADLE, suggesting that chemical modification of DADLE a t the C terminus did not markedly affect its pharmacological activity. Thes e DADLE derivatives were more stable than native DADLE in jejunal and colon ic homogenates. A "bell-shaped" profile was observed between the apparent p ermeability coefficients (Papp) of DADLE derivatives and lipophilicity. In particular, DADLE-C4 had the greatest permeability characteristics across t he intestinal membrane of the acyl derivatives studied in this experiment. The permeability of DADLE-C4 across the jejunal membrane was further improv ed 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.