ORALLY-ACTIVE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .2. DISPOSITION OF L-694,458 IN RATS AND RHESUS-MONKEYS

The disposition of L-694,458, a potent monocyclic beta-lactam inhibito r of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After iv dosing, L-694,458 exhibited similar phar macokinetic 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 a nd 34 ml/min/kg, 2.3 hr, and 5 liters/kg in rhesus monkeys. The bioava ilability of a 10 mg/kg oral dose was higher in rats (65%) than in rhe sus monkeys (39%). In both species, concentrations of L-694,458 in pla sma increased more than proportionally when the oral dose was increase d from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concentrat ion-time profile was observed at 40 mg/kg, characterized by a delayed T-max (8-24 hr) and a long terminal half-life (6 hr). [H-3]L-694,458 w as well absorbed after oral dosing to rats at 10 mg/kg, as indicated b y the high recovery of radioactivity in bile (83%) and urine (6%) of b ile duct-cannulated rats. Only similar to 5% or less of the radioactiv ity in bile, urine, and feces was a result of intact L-694,458, indica ting that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile. Demethylenation of t he methylenedioxyphenyl group resulting in the catechol was the primar y metabolic pathway in human and rhesus monkey liver microsomes. In ra t liver microsomes, the major metabolite was the N-oxide of the methyl -substituted piperazine nitrogen. In rats dosed iv and orally with [H- 3]L-694,458, concentrations of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstab le in rat blood and plasma, degrading via a pathway believed to be cat alyzed by B-esterases and to involve cleavage of the beta-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indic ated that in human liver, L-694,458 was metabolized by CYP3A and 2C is ozymes, and in both monkey and human liver microsomes the compound act ed as an inhibitor of testosterone 6 beta-hydroxylation.