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
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.