RT Journal Article
SR Electronic
T1 Orally Active Inhibitors Of Human Leukocyte Elastase. II. Disposition of L-694,458 in Rats and Rhesus Monkeys
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 932
OP 939
VO 25
IS 8
A1 Styliani H. Vincent
A1 Susan K. Painter
A1 Debra Luffer-Atlas
A1 Bindhu V. Karanam
A1 E. McGowan
A1 Chris Cioffe
A1 George Doss
A1 Shuet-Hing L. Chiu
YR 1997
UL http://dmd.aspetjournals.org/content/25/8/932.abstract
AB The disposition of L-694,458, a potent monocyclic β-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After iv dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and volume of distribution at steady state were 27 ml/min/kg, 1.8 hr, and 4.0 liters/kg in rats and 34 ml/min/kg, 2.3 hr, and 5 liters/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concentrations of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concentration-time profile was observed at 40 mg/kg, characterized by a delayed Tmax (8–24 hr) and a long terminal half-life (6 hr). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only ∼5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile. Demethylenation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed iv and orally with [3H]L-694,458, concentrations of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the β-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and 2C isozymes, and in both monkey and human liver microsomes the compound acted as an inhibitor of testosterone 6β-hydroxylation. The American Society for Pharmacology and Experimental Therapeutics