Des-enkephalin-gamma-endorphin (DE gamma E): pharmacokinetics in dogs after intravenous and subcutaneous administration.

After intravenous dosing in dogs [3H-Lys9]-DE gamma E (Org 5878) was very rapidly eliminated from the circulation. Disappearance of the neuropeptide from blood followed a biphasic decay with half-lives of 0.6 +/- 0.1 min (+/- S.D.; alpha-phase) and 2.4 +/- 1.0 min (beta-phase). The central volume of distribution ranged between 0.05 and 0.23 l.kg-1. The mean blood clearance rate amounted to 0.15 l.min-1.kg-1, which is indicative of extensive hepatic and extrahepatic metabolism of DE gamma E. In contrast to intravenous dosing, subcutaneous injection of [3H]-DE gamma E in dogs resulted in low but relatively long-lasting peptide levels in blood. Peak values were found at 5-10 min, whereafter they declined to the limit of detection at 1.5-2 h. The bioavailability of DE gamma E for this route of administration was shown to be 20-23%.

Assay of vecuronium in plasma using solid-phase extraction, high-performance liquid chromatography and post-column ion-pair extraction with fluorimetric detection.

An assay has been developed and validated for the routine monitoring of vecuronium in plasma. It consists of solid-phase extraction using C18 disposables as sample pre-treatment, high-performance liquid chromatography and post-column ion-pair extraction with fluorimetric detection. The fluorescent anion 9,10-dimethoxyanthracene-2-sulphonate (DAS) is used as the counter ion. The detection limit is ca. 5 ng/ml in plasma with a signal-to-noise ratio of 10. The assay is also applicable for monitoring vecuronium and its potential metabolites in other biological media, e.g., urine, bile and tissue (liver, kidney) homogenates.

Des-enkephalin-gamma-endorphin (DE gamma E): biotransformation in rat, dog and human plasma.

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.

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

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-gamma-endorphin: bioavailability in rats following the subcutaneous and intramuscular route of administration.

A pharmacokinetic study with [3H]des-enkephalin-gamma-endorphin (3H-DE gamma E) was performed in rats after the intravenous, subcutaneous and intramuscular route of administration. Disappearance of non-metabolized 3H-DE gamma E from blood upon intravenous dosing followed a biphasic decay with half-lives of 0.7 +/- 0.3 (+/- S.D.) min for the initial distribution phase and 6.3 +/- 2.7 min for the terminal elimination phase. The central and peripheral volumes of distribution were strikingly high (0.38 and 0.55 1 X kg-1, respectively). Extensive metabolism occurred already within the first minutes after injection. The blood clearance rate was found to be 0.29 +/- 0.12 1 X min-1 X kg-1, which value points to remarkable extrahepatic elimination of the neuropeptide. As compared to the intravenous route of administration, subcutaneous or intramuscular injection of 3H-DE gamma E resulted in low but longer-lasting peptide levels in blood. These levels reached already peak values at 2 min after both routes of administration and then declined to below the limit of detection at 2-3 h. The absolute bioavailability of DE gamma E after subcutaneous injection amounted to 30.9 +/- 16.3% (range 16.0-46.9%), whereas the bioavailability after intramuscular injection was observed to be 3.5 times lower (8.5 +/- 3.0%; range 4.6-12.0%). These data suggest that subcutaneous dosing of DE gamma E might be more effective in displaying CNS activity than the intramuscular route.

The metabolism of mianserin in women, rabbits, and rats: identification of the major urinary metabolites.

The biotransformation of orally administered 3H-mianserin was investigated in female human subjects, rabbits, and rats by identification of the major urinary metabolites. Three days after dosing, the urinary excretion of radioactivity was 53% in women, 36% in rats, and 80% in rabbits. In the women's urine, 15% of the administered dose was excreted in the form of mianserin (conjugated plus nonconjugated); in the animal species this quantity was 1-2%. Mianserin was predominantly metabolized to 8-hydroxy analogs in all species; in rats, 8-hydroxydesmethylmianserin was the principal metabolite. Demethylation was an important metabolic pathway in the animal species, but not in women. Novel N-formyl compounds were detected in the urine of both animal species, but the possibility that these were artifacts formed during extraction with chloroform cannot be ruled out. Trace amounts of two compounds in which the piperazine moiety of mianserin was absent, 11H-dibenz[b,e]azepine and 11 H-dibenz[b,e]azepine-2-ol, were identified in the urine of rabbits and rats, respectively.