Document 0788
 DOCN  M95A0788
 TI    Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease
       inhibitor, in rats, dogs and monkeys.
 DT    9510
 AU    Lin JH; Chiba M; Chen IW; Vastag KJ; Nishime JA; Dorsey BD; Michelson
       SR; McDaniel SL; Merck Research Laboratories, West Point, Pennsylvania,
       USA.
 SO    J Pharmacol Exp Ther. 1995 Jul;274(1):264-9. Unique Identifier :
       AIDSLINE MED/95341504
 AB    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)
 DE    Administration, Oral  Animal  Dogs  Dose-Response Relationship, Drug
       Haplorhini  HIV Protease Inhibitors/ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS  Indans/ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS  Infusions, Intravenous  Microsomes,
       Liver/METABOLISM  Molecular Structure  Piperazines/ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS  Rats  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).