title: The outstanding metabolic stability of a 14C-labeled beta-nonapeptide in rats--in vitro and in vivo pharmacokinetic studies.
abstract: METHODS
  In CaCo-2 cell monolayers the beta-nonapeptide H(beta-HAla-beta-HLys-beta-HPhe)(3)-OH.4HCl (1), (14)C-labeled on both C atoms of the CH(2)-CO moiety of the central beta-HPhe residue, showed a low intrinsic permeability (<1%) and is subject to a prominent efflux system. The beta-peptide (1) binds to human and rat plasma protein in vitro independent of the concentration of 1 and of the species (30-36% bound fraction at 50, 500, and 5000 ng/ml), and has only low affinity for the corresponding blood cells (less than 5% of compound 1 in blood cells).
  
  
  METHODS
  The in vivo pharmacokinetic characteristics after i.v. administration of 5 mg/kg (to male rats and to bile-duct-operated rats) were: (i) negligible in vivo biotransformation of 1 (in urine, plasma and feces unchanged 1 represented virtually the only compound-related molecule); (ii) rapid initial decline (0-8 h post dose) of levels of compound 1 in blood and plasma followed by a slower decline (8-96 h post dose); (iii) in non-operated animals after 96 h only 38% of the dose was excreted and after 168 h 49% of the dose was found remaining in the carcass; elimination through the intestine wall represented the major elimination pathway in non-operated animals while in bile-duct-cannulated animals biliary excretion was not found to contribute substantially to elimination (iv) quantitative whole-body autoradioluminography (QWBAL) investigations revealed that the kidney was by far the most important target organ of distribution; other tissues with high concentrations of compound-related radioactivity were cartilage, lymph nodes, and liver, whereas lowest levels were found in white fat and in the brain. After p.o. administration (10 mg/kg) negligible radioactivity was observed in the systemic circulation, indicating negligible absorption; essentially the entire oral dose was recovered unchanged in feces collected over a period of 96 h.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland.
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: Gian P
authors.initials: GP
authors.lastname: Camenisch
authors.forename: Maria I
authors.initials: MI
authors.lastname: Rodriguez Perez
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
authors.forename: Ralph
authors.initials: R
authors.lastname: Woessner
authors.forename: Rolf
authors.initials: R
authors.lastname: Voges
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Jens
authors.initials: J
authors.lastname: Frackenpohl
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D002463:Cell Membrane Permeability; D004355:Drug Stability; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D009842:Oligopeptides