PHARMACOKINETICS AND DISPOSITION OF L-692,429 - A NOVEL NONPEPTIDYL GROWTH-HORMONE SECRETAGOGUE IN PRECLINICAL SPECIES

L-692,429 is a novel nonpeptidyl growth hormone secretagogue that has been demonstrated to stimulate growth hormone secretion in rats, dogs, and humans after intravenous administration. We have examined the pha rmacokinetics and disposition of L-692,429 in male Sprague-Dawley rats , beagle dogs, and chimpanzees. Plasma clearance (CL(p)) of L-692,429 in dogs after intravenous dosing was similar to 18 ml/min/kg and was c onstant between the doses of 0.1 and 0.9 mg/kg. In rats, CL(p) after i ntravenous dosing increased from 3 to 12 ml/min/kg in a dose-dependent manner between 0.1 and 5 mg/kg. In chimpanzees, CL(p) after an intrav enous dose of L-692,429 at 0.5 mg/kg was 5.7 ml/min/kg. In vitro bindi ng of L-692,429 to plasma proteins of dogs, chimpanzees, and humans wa s similar to 87%, 94%, and 93.5%, respectively, and was independent of concentration. In contrast, plasma binding of L-692,429 was concentra tion-dependent in rats and decreased from 98.5% to 90.6% between 0.01 and 10 mu g/ml. Metabolism of L-692,429 was minimal in rats, but moder ate in dogs, with the major metabolite being a derivative monohydroxyl ated at the benzolactam moiety. Thus, the faster clearance of L-692,42 9 in dogs likely is caused by less extensive plasma protein binding an d higher metabolic clearance. The nonlinear pharmacokinetics in rats p robably is the result of concentration-dependence in plasma binding. T he results of these studies suggest that plasma protein binding plays a major role in determining the values of CL(p) of L-692,429 among the species. After an intravenous dose of [H-3]L-692,429 to rats, liver, kidney, lung, and heart had the highest levels of radioactivity at the early time points, but the gastrointestinal tract had increasing conc entrations at later time points. Most of the radioactivity was cleared from all tissues by 24 hr, indicating that L-692,429 did not accumula te in tissues. After intravenous dosing of [H-3]L-692,429 to rats and dogs, recoveries of total radioactivity in urine and feces corresponde d to similar to 10% and 90%, respectively. Greater than 70% of radioac tivity was recovered in bile of rats within 24 hr after intravenous do sing of [H-3]L-692,429, indicating that biliary excretion was the prim ary route of elimination. Based on the combined recoveries of the radi oactive dose in bile and urine after an oral dose of L-692,429, oral a bsorption in rats was similar to 3%. The poor absorption may be the re sult of the zwitterionic nature of this compound.