ORALLY-ACTIVE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .1. DISPOSITION OF (L)-683,845 IN RATS AND RHESUS-MONKEYS

L-683,845 is an orally active inhibitor of human leukocyte elastase. I ts disposition was studied in rats and rhesus monkeys after dosing wit h a H-3- or C-14-labeled compound intravenously at 5 mg/kg and orally at 10 mg/kg. L-683,845 exhibited different pharmacokinetics in these t wo species. In rats, L-683,845 was well-absorbed after oral dosing, wi th a maximum concentration of 6 mu g/ml at 2 hr and bioavailability of similar to 100%. After intravenous dosing, it was cleared slowly at s imilar to 3 ml/min/kg, with a terminal half-life of similar to 7 hr an d a volume of distribution at steady-state of 1 liter/kg. After both i ntravenous and oral dosing, L-683,845 comprised 50-95% of plasma radio activity. About 75% of the intravenous and 87% of the oral dose were r ecovered 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 mu g/ml, and b ioavailability was 50%. Plasma clearance was 8-fold higher, at 23 ml/m in/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 det ermined accurately after intravenous dosing, but seemed to be long in orally dosed animals, similar to 13 hr. Intact L-683,845 was a minor c omponent in plasma comprising only similar to 20% of the radioactivity at most time points. Moreover, persistent levels of radioactivity wer e detected in plasma and urine of rhesus monkeys even at 1-month postd ose, and greater than or equal to 25% of the radioactivity in plasma w as irreversibly bound to proteins at the later time points. Recovery o f the radioactivity was incomplete, with only 77% of the intravenous a nd 43% of the oral dose recovered over a 4-day period. L-683,845-deriv ed radioactivity distributed to all major rat tissues, with highest le vels 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 mu g eq/g. A large portion of the intravenous dose was re covered in the small intestine, similar to 40% at 2 hr, indicating rap id and extensive biliary excretion. L-683,845 was metabolized primaril y to the acyl glucuronide, which was very unstable in rat plasma, and was subject to hydrolysis to L-683,845 and rearrangement. The glucuron ide and L-683,845 were degraded in rat plasma by opening the beta-lact am 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 th eir degradation is catalyzed by a type B esterase.