Development of novel lipophilic derivatives of DADLE (leucine enkephalin analogue): intestinal permeability characateristics of DADLE derivatives in rats.
OBJECTIVE
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.
Uchiyama
T
T
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
Kotani
A
A
Tatsumi
H
H
Kishida
T
T
Okamoto
A
A
Okada
N
N
Murakami
M
M
Fujita
T
T
Fujiwara
Y
Y
Kiso
Y
Y
Muranishi
S
S
Yamamoto
A
A
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003106:Colon / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016308:Enkephalin, Leucine-2-Alanine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008566:Membranes / Q000378:metabolism; D051381:Rats
D008055:Lipids; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine