[3H]9-desglycinamide,8-arginine vasopressin: metabolism and in-vivo fate

Abstract

Half-lives based on the disappearance of [3H]9-desglycinamide,8-arginine vasopressin ([3H]DGAVP) following in-vitro incubation in plasma were 1.7 h (dog), 5.8 h (rat) and greater than 12 h (man). For all three species, and particularly dogs, biotransformation of the peptide in plasma occurred predominantly through carboxypeptidase activities, leading to the accumulation of AVP-(1-7). Disappearance of [3H]DGAVP from rat blood after a single i.v. injection followed a biphasic decay with half-lives of 2.2 +/- 0.8 (S.D.) min (distribution phase) and 14.4 +/- 1.2 min (elimination phase). The central and peripheral volumes of distribution were high and of the same order of magnitude, being 0.21 and 0.25 litres/kg respectively. Blood clearance values ranged from 36 to 45 ml/min per kg. In addition to [3H]AVP-(1-7), [3H]tyrosine was also found to be a major radioactive metabolite in blood. Compared with i.v. dosing, the s.c. route of administration for [3H]DGAVP resulted in longer-lasting peptide levels in blood which persisted for up to 4-5 h after injection. Maximal concentrations were reached at 7.5 min, whereafter they declined bi-exponentially with terminal half-lives of 31.1 +/- 8.7 min. The mean bioavailability for DGAVP was almost 100%, demonstrating virtually complete absorption from the s.c. injection site.

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

“…administration to dogs DEyE disappears very rapidly from the blood circulation. The elimination half-life of the peptide in this species amounts to 2.4 ± 1.0 min, which is about 2.5 times lower than previously observed in rats (7). Moreover, s,c.…”

“…These values are of the same older of magnitude as established for DEyE in rats (30.9 ± 16.3%; ref. 7).…”

“…Subcutaneous or intramuscular administration, however, resulted in longer-lasting blood peptide levels. The bioavailability of DEyE for the subcutaneous route of administration was approximately 31%, whereas the bioavailability after intramuscular injection appeared to be 3.5 times lower (7).…”

“…Subsequently, the TCA supernatants were prepurified on Seppak-Cis cartridges (Waters, Milford, USA) as described elsewhere (7). The DEyE containing fractions were evaporated to dryness at 400C in a Speed Vac Concentrator (Dumee, Soest, The Netherlands) and stored at -20°C until HPLC analysis.…”

“…Recent in vivo fate studies with tritiated DEyE in rats demonstrated extensive distribution and biotransformation of this neuropeptide (6,7). After intravenous injection the elimination half-life was found to be 6.3 min.…”