Des-enkephalin-γ-endorphin (DEγE): Biotransformation in rat, dog and human plasma

Abstract

Biotransformation of [3H-Lys9] DE gamma E was investigated after in vitro incubation of the tritiated peptide with rat, dog and human plasma. In addition, its metabolite profile in blood was studied following intravenous administration to rats and dogs. Half-lives for the in vitro disappearance of DE gamma E in plasma were 13.0 +/- 0.8 min (dog), 15.7 +/- 1.2 min (rat) and 19.2 +/- 0.9 min (human), indicating very rapid degradation of the peptide by proteolytic enzymes. Biotransformation products were identified on the basis of co-chromatography on HPLC with synthetic reference peptides. The six principal fragments appeared to be beta-endorphin (beta E) sequences 7-17, 8-17, 9-17, 6-15, 7-15 and 8-15. The abundance of beta E6-15, beta E7-15 and beta E8-15 in rat and human plasma suggests preferential, subsequent carboxypeptidase and aminopeptidase mechanisms, whereas in dog plasma DE gamma E is predominantly degraded by aminopeptidase activities (major peptide metabolites: beta E7-17 and beta E8-17). In the in vivo studies with rats and dogs the same radioactive peptide fragments were detected in blood as found in the in vitro experiments with plasma. In both species their blood levels were already maximal within a minute after intravenous administration of the parent peptide, thereafter they declined rapidly. 3H-Lysine was the main radioactive metabolite in vivo, exceeding 70% of total radioactivity in rat and dog blood 10 min after 3H-DE gamma E dosing.

Des-enkephalin-γ-endorphin (DEγE): Pharmacokinetics in dogs after intravenous and subcutaneous administration

“…This is also in agreement with the observed higher rate of in vitro metabolic degradation of DEyE in dog plasma than in rat plasma (13). Comparable species-dependent differences in the in vivo elimination of peptides have been noticed for the vasopressin derivative DGAVP, which shows half-lives of about 8 min in dogs (14) and 15 min in rats (15).…”

Transport of peptide and protein drugs across biological membranes

“…5 with DEyE data from our labaratory. The degradation half -life of the latter peptide, both in epidermis and dermis, was surprisingly long as compared to that in human-plasma (7,85). Thus improvement of transdermal peptide delivery will most likely occur by facilitating its percutaneous transport, intra (epi-)dermal biotransformation being a problem of minor importance.…”