title: Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys.
abstract: 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 microM) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Chiba
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: K J
authors.initials: KJ
authors.lastname: Vastag
authors.forename: J A
authors.initials: JA
authors.lastname: Nishime
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: S R
authors.initials: SR
authors.lastname: Michelson
authors.forename: S L
authors.initials: SL
authors.lastname: McDaniel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000882:Haplorhini; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase
chemical_list: D017320:HIV Protease Inhibitors; D007189:Indans; C094644:L 754394; D010879:Piperazines; D039181:Steroid 16-alpha-Hydroxylase