The outstanding metabolic stability of a 14C-labeled beta-nonapeptide in rats--in vitro and in vivo pharmacokinetic studies.

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). 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.