The outstanding metabolic stability of a 14C‐labeled β‐nonapeptide in rats – in vitro and in vivo pharmacokinetic studies

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Abstract
In vitro studies: In CaCo‐2 cell monolayers the β‐nonapeptide H(β‐HAla‐β‐HLys‐β‐HPhe)3‐OH·4HCl (1), 14C‐labeled on both C atoms of the CH2–CO moiety of the central β‐HPhe residue, showed a low intrinsic permeability (β‐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). In vivo studies: 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. Copyright © 2002 John Wiley & Sons, Ltd.

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