Whole body and brain distribution of [³H]cyclic [D-Pen²,D-Pen⁵] enkephalin after intraperitoneal, intravenous, oral and subcutaneous administration

The route of administration of a given drug can have a significant influence upon whole body distribution. The present study examined whole body distribution of the δ opioid receptor-selective peptide [³H]DPDPE in male CD1 mice after administration by several routes. Additionally, we describe regional brain distribution of [³H]DPDPE after i.v. administration with and without pretreatment with naloxone or the selective δ receptor antagonist naltrindole. Finally, characterization of the inherent enzymatic stability of DPDPE was also examined. Intravenous administration results in a significantly large amount of [³H]DPDPE in the small intestine and flush at 15 and 30 min postadministration, suggesting rapid biliary excretion. The highest level in the brain after i.v. administration occurred at 60 min (0.08%). After i.p. and s.c. administration, large amounts of [³H]DPDPE were found in the small intestine and flush, but not until 60 min postadministration, suggesting a slower rate of absorption from the site of administration. The i.p. and s.c. groups' brain levels peaked at 120 min (0.07 and 0.09%, respectively). The highest levels in the brain after p.o. administration were seen at 240 min (0.03%). Examination of regional brain distribution data showed no significant difference in the levels of [³H]DPDPE between brain regions at any time point studied. However, naloxone pretreatment resulted in significant reductions of [³H]DPDPE in all brain regions at 5 and 10 min. Naltrindole pretreatment resulted in significant reductions in the frontal cortex and striatum at 5 and/or 10 min postadministration, but had no effect on [³H]DPDPE levels in cerebellum, hippocampus or brain stem. The incubation of DPDPE and its noncyclized, reduced form in mouse serum revealed that the presence of the disulfide bridge between D-Pen² and D-Pen⁵ is an extremely important determinant of DPDPE's resistance to enzymatic degradation. The results from this study suggest that the route of administration can play a significant role in the time course distribution of [³H]DPDPE to the small intestine and the brain, and the inherent stability of DPDPE is due to its cyclized nature resulting from the presence of a disulfide bridge.