title: Orally active inhibitors of human leukocyte elastase. I. Disposition of L-683,845 in rats and rhesus monkeys.
abstract: L-683,845 is an orally active inhibitor of human leukocyte elastase. Its disposition was studied in rats and rhesus monkeys after dosing with a 3H- or 14C-labeled compound intravenously at 5 mg/kg and orally at 10 mg/kg. L-683,845 exhibited different pharmacokinetics in these two species. In rats, L-683,845 was well-absorbed after oral dosing, with a maximum concentration of 6 microg/ml at 2 hr and bioavailability of approximately 100%. After intravenous dosing, it was cleared slowly at approximately 3 ml/min/kg, with a terminal half-life of approximately 7 hr and a volume of distribution at steady-state of 1 liter/kg. After both intravenous and oral dosing, L-683,845 comprised 50-95% of plasma radioactivity. About 75% of the intravenous and 87% of the oral dose were recovered in the feces as parent and/or conjugates, with the remaining fraction recovered in the urine as polar components. In rhesus monkeys, maximum concentration after oral dosing was only 0.25 microg/ml, and bioavailability was 50%. Plasma clearance was 8-fold higher, at 23 ml/min/kg, and volume of distribution at steady-state larger, at 2 liters/kg, than in rats. The terminal half-life of L-683,845 could not be determined accurately after intravenous dosing, but seemed to be long in orally dosed animals, approximately 13 hr. Intact L-683,845 was a minor component in plasma comprising only approximately 20% of the radioactivity at most time points. Moreover, persistent levels of radioactivity were detected in plasma and urine of rhesus monkeys even at 1-month postdose, and > or = 25% of the radioactivity in plasma was irreversibly bound to proteins at the later time points. Recovery of the radioactivity was incomplete, with only 77% of the intravenous and 43% of the oral dose recovered over a 4-day period. L-683,845-derived radioactivity distributed to all major rat tissues, with highest levels in the liver followed by the small intestine, adrenals, kidneys, and lungs. Radioactivity concentrations in the liver were high even at 24 hr, 22.7 microg eq/g. A large portion of the intravenous dose was recovered in the small intestine, approximately 40% at 2 hr, indicating rapid and extensive biliary excretion. L-683,845 was metabolized primarily to the acyl glucuronide, which was very unstable in rat plasma, and was subject to hydrolysis to L-683,845 and rearrangement. The glucuronide and L-683,845 were degraded in rat plasma by opening the beta-lactam ring and loss of the C4 substituent followed by decarboxylation to give an olefin and/or decomposition to the monosubstituted urea. Based on inhibition by organophosphorus compounds, it is speculated that their degradation is catalyzed by a type B esterase.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Vincent
authors.forename: S K
authors.initials: SK
authors.lastname: Painter
authors.forename: P A
authors.initials: PA
authors.lastname: Krieter
authors.forename: A E
authors.initials: AE
authors.lastname: Colletti
authors.forename: E
authors.initials: E
authors.lastname: Lyszack
authors.forename: A
authors.initials: A
authors.lastname: Rosegay
authors.forename: D
authors.initials: D
authors.lastname: Dean
authors.forename: D
authors.initials: D
authors.lastname: Luffer-Atlas
authors.forename: R R
authors.initials: RR
authors.lastname: Miller
authors.forename: C
authors.initials: C
authors.lastname: Cioffe
authors.forename: S H
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005965:Glucuronates / Q000097:blood; D006207:Half-Life; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D005965:Glucuronates; C104775:L 683845; D019272:Leukocyte Elastase