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 pharmacokinetics and disposition of L-692,429 in male Sprague-Dawley rats, beagle dogs, and chimpanzees. Plasma clearance (CLp) of L-692,429 in dogs after intravenous dosing was approximately 18 ml/min/kg and was constant between the doses of 0.1 and 0.9 mg/kg. In rats, CLp after intravenous dosing increased from 3 to 12 ml/min/kg in a dose-dependent manner between 0.1 and 5 mg/kg. In chimpanzees, CLp after an intravenous dose of L-692,429 at 0.5 mg/kg was 5.7 ml/min/kg. In vitro binding of L-692,429 to plasma proteins of dogs, chimpanzees, and humans was approximately 87%, 94%, and 93.5%, respectively, and was independent of concentration. In contrast, plasma binding of L-692,429 was concentration-dependent in rats and decreased from 98.5% to 90.6% between 0.01 and 10 micrograms/ml. Metabolism of L-692,429 was minimal in rats, but moderate in dogs, with the major metabolite being a derivative monohydroxylated at the benzolactam moiety. Thus, the faster clearance of L-692,429 in dogs likely is caused by less extensive plasma protein binding and higher metabolic clearance. The nonlinear pharmacokinetics in rats probably is the result of concentration-dependence in plasma binding. The results of these studies suggest that plasma protein binding plays a major role in determining the values of CLp of L-692,429 among the species. After an intravenous dose of [3H]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 concentrations at later time points. Most of the radioactivity was cleared from all tissues by 24 hr, indicating that L-692,429 did not accumulate in tissues. After intravenous dosing of [3H]L-692,429 to rats and dogs, recoveries of total radioactivity in urine and feces corresponded to approximately 10% and 90%, respectively. Greater than 70% of radioactivity was recovered in bile of rats within 24 hr after intravenous dosing of [3H]L-692,429, indicating that biliary excretion was the primary route of elimination. Based on the combined recoveries of the radioactive dose in bile and urine after an oral dose of L-692,429, oral absorption in rats was approximately 3%. The poor absorption may be the result of the zwitterionic nature of this compound.
Leung
K H
KH
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA.
Cohn
D A
DA
Miller
R R
RR
Doss
G A
GA
Stearns
R A
RA
Simpson
R E
RE
Feeney
W P
WP
Chiu
S H
SH
D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005243:Feces; D013006:Growth Hormone / Q000172:deficiency; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D002679:Pan troglodytes; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D014556:Urine
D001552:Benzazepines; D001798:Blood Proteins; D013777:Tetrazoles; C081455:L 692429; D013006:Growth Hormone