Time-Dependent And Dose-Dependent Pharmacokinetics Of L-754,394, An Hiv Protease Inhibitor, In Rats, Dogs And Monkeys

L-754,394 is a potent and specific inhibitor of the HIV-1 encoded protease that is essential for the maturation of the infectious virus. The drug exhibited dose-dependent kinetics in all species studied (rat, dog and monkey); the apparent clearance decreased when the dose was increased. However, the dose-dependency cannot be explained by Michaelis-Menten kinetics. L-754,394 in plasma declined log-linearly with time, but with an apparent half-life that increased with dose. The apparent terminal half-life of L-754,394 in rats increased from 20 min at 0.5 mg/kg i.v, to 118 min at 10 mg/kg i.v. Furthermore, L-754,394 exhibited time-dependent pharmacokinetics. After chronic i.v, doses for 7 days (1 mg/kg/dose/day), the apparent clearance of L-754,394 in rats decreased from 87 ml/min/kg after the first dose to 25 ml/min/kg after the last dose. Similar results were observed in dogs and monkeys. In vitro spectral studies indicated that approximately 40 to 60% of the content of cytochrome P-450 was inactivated when L-754,394 (10 mu M) was incubated with rat, dog and monkey liver microsomes in the presence of NADPH. Little or no inactivation of cytochrome P-450 was observed when either NADPH or L-754,394 was omitted. In addition, L-754,394 selectively inhibited CYP 2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylase activity and CYP 3A1/2-dependent testosterone 6 beta-hydroxylase activity, but not CYP 2D1/2-dependent bufuralol 1'-hydroxylase activity nor CYP 1A2-dependent phenacetin O-deethylase activity in rat liver microsomes. Taken together, these results suggest that L-754,394 is a mechanism-based inactivator, and the time- and dose-dependent kinetics of L-754,394 may be explained by mechanism-based enzyme inactivation.