Sh. Vincent et al., ORALLY-ACTIVE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .2. DISPOSITION OF L-694,458 IN RATS AND RHESUS-MONKEYS, Drug metabolism and disposition, 25(8), 1997, pp. 932-939
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.