Document 0707
 DOCN  M9550707
 TI    A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas,
       in rats and dogs.
 DT    9505
 AU    Wong YN; Burcham DL; Saxton PL; Erickson-Viitanen S; Grubb MF; Quon CY;
       Huang SM; Drug Metabolism and Pharmacokinetics Section, DuPont Merck;
       Pharmaceutical Company, Newark, DE 19714.
 SO    Biopharm Drug Dispos. 1994 Oct;15(7):535-44. Unique Identifier :
       AIDSLINE MED/95151981
 AB    The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors
       of HIV protease were studied in rats or dogs after intravenous and oral
       administration. Six symmetrically substituted cyclic urea compounds
       (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively
       inhibited HIV virus replication, with IC90 values of 0.03-1.0 microM
       (0.017-0.76 microgram mL-1), were evaluated. Plasma concentrations were
       measured in rats and dogs using specific and sensitive HPLC methods. In
       rats, the maximum plasma concentrations of 0.21-1.88 micrograms mL-1
       were detected within 1 h of oral administration of 10 mg kg-1 of the
       compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats
       and the absolute oral bioavailability ranged from 18 to 100%. In dogs,
       the maximum plasma concentration and absolute oral bioavailability were
       4.37 micrograms mL-1 and 48%, 1.07 micrograms mL-1 and 16%, and 1.48 mg
       ML-1 and 38% for XK234, XM311, and XM323, respectively. The data
       demonstrated that the maximum plasma concentrations of these cyclic
       ureas were several times higher than the IC90 for inhibition of viral
       replication after single doses of 10 mg kg-1 in rats and dogs. With this
       combination of high potency against virus replication and good oral
       bioavailability, these cyclic ureas represent a new class of compounds
       that are suitable for development as therapeutic agents for the
       treatment of HIV-associated diseases.
 DE    Administration, Oral  Animal  Biological Availability  Chromatography,
       High Pressure Liquid  Computer Simulation  Cross-Over Studies  Dogs
       Half-Life  HIV/DRUG EFFECTS  HIV Protease Inhibitors/ADMINISTRATION &
       DOSAGE/BLOOD/  PHARMACOLOGY/*PHARMACOKINETICS  Injections, Intravenous
       Male  Rats  Rats, Sprague-Dawley  Structure-Activity Relationship
       Urea/*ANALOGS & DERIVATIVES  Virus Replication/DRUG EFFECTS  JOURNAL
       ARTICLE

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