Des-Tyr1-γ-endorphin (DTγE) and des-enkephalin-γ-endorphin (DEγE): plasma profile and brain uptake after systemic administration in the rat

Abstract The plasma disappearance, metabolism and uptake in the brain of [ 3 H-Phe 4 ]-DTγE and [ 3 H-Lys 9 ]-DEγE were investigated following systemic administration of these neuroleptic-like peptides to rats. 3 H-DTγE, 3 H-DEγE and their radioactive metabolites in plasma and brain extracts were determined by reversed-phase HPLC. Plasma disappearance of DTγE upon intravenous (IV) dosing followed a biphasic pattern with half-lives of 0.7 min (distribution phase) and 5.5 min (elimination phase). For DEγE the plasma disappearance curve was best characterized by a one-compartment model since a second elimination phase was hardly detectable by our methods. The corresponding half-life was 0.6 min, probably representative for the initial distribution phase of DEγE. Both neuropeptides distributed rapidly over the larger part of the extracellular fluid. Following the IV route of administration, brain uptake of DTγE and DEγE appeared to be low. Brain levels of DTγE decreased from 0.0075% to 0.0031% of the administered dose/g tissue at 2–15.5 min after injection, whereas those of DEγE decreased very rapidly from 0.0174% of the dose/g brain tissue to below the detection limit at 2–4.5 min after injection. As compared to the IV route of administration, subcutaneous (SC) injection of DEγE resulted into lower but remarkably longer-lasting peptide concentrations in plasma as well as in brain, possibly because of a sustained release from the SC site of injection. These observations suggest that the SC route of administration might be more effective in displaying CNS activites of DEγE than IV administration. From the 3 H-metabolite profiles in plasma and brain after systemic administration of [ 3 H-Phe 4 ]-DTγE or [ 3 H-Lys 9 ]-DEγE, it was apparent that free 3 H-phenylalanine or 3 H-lysine were the sole significant metabolites. In addition, a limited number of minor 3 H-peptide intermediates were persistently found in trace amounts, possibly being N-terminal fragments of DTγE and DEγE.