title: Pharmacokinetic investigation of a 14C-labelled beta 3/alpha tetrapeptide in rats.
abstract: The solid-phase synthesis and an ADME investigation with albino and pigmented male rats of the doubly 14C-labelled beta/alpha-tetrapeptide derivative Ac-beta3 hTyr-(D)Trp-beta3 hLys-beta3 hThr-lactone (3; Fig. 3) are described. After intravenous (i.v.) and peroral (p.o.) administration of the peptide, its concentration in blood and plasma, its tissue distribution, and the metabolism and the excretion of the peptide were analyzed over a period of up to 7 days post dose. The tetrapeptide in its ring opened form, 5, has a bioavailability of ca. 25%; radioactivity is distributed in the animals in an organ-specific way, and the compound appears to pass the blood-brain barrier to a very small extent, if at all (Tables 1-3 and Figs. 2-6). Excretion (37% renal, 44% fecal, including biliary) of the tetrapeptide 4 days after i.v. administration is almost complete, with only 4.3% remaining in the carcass; 4 days after p.o. administration 97% of the dose has been excreted in the feces. Radiochromatograms taken of plasma (0.5 and 24 h after i.v. dosing) and of urine and feces extracts (0-48 h collected) reveal the presence of lactone 3 and/or the corresponding hydroxy acid 5 with essentially no or very minor other peaks, respectively, representing possible metabolites (Tables 4-6, and Fig. 7 and 8). A comparison with a previous ADME investigation of a beta-nonapeptide show that--except for the lack of metabolism--all aspects of exposure, distribution, and elimination are different (structure-specific properties). The investigated tetrapeptide 3 is a potent and highly specific agonist of the somatostatin receptor hsst4, rendering the results described herein promising for diagnostic and therapeutic applications of beta-peptides.
authors.affiliation: Preclinical Safety Europe, Novartis Pharma AG, Postfach, CH-4002 Basel.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Wiegand
authors.forename: Bernard
authors.initials: B
authors.lastname: Wirz
authors.forename: Alain
authors.initials: A
authors.lastname: Schweitzer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
authors.forename: Maria I Rodriguez
authors.initials: MI
authors.lastname: Perez
authors.forename: Hendrik
authors.initials: H
authors.lastname: Andres
authors.forename: Thierry
authors.initials: T
authors.lastname: Kimmerlin
authors.forename: Magnus
authors.initials: M
authors.lastname: Rueping
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D002250:Carbon Radioisotopes; D009842:Oligopeptides