Document 0151
 DOCN  M9550151
 TI    Pharmacokinetics of HIV protease inhibitor DMP 323 in rats and dogs.
 DT    9505
 AU    Grubb MF; Wong YN; Burcham DL; Saxton PL; Quon CY; Huang SM; Drug
       Metabolism and Pharmacokinetics Section, DuPont Merck; Pharmaceutical
       Company.
 SO    Drug Metab Dispos. 1994 Sep-Oct;22(5):709-12. Unique Identifier :
       AIDSLINE MED/95136855
 AB    DMP 323 is a symmetrically substituted cyclic urea compound with
       demonstrated activity against human immunodeficiency virus (HIV) in
       vitro. DMP 323 has been measured in rat and dog plasma via liquid-liquid
       extraction and HPLC. The limit of quantitation is 10 ng/ml using 0.5 ml
       plasma. Following an intravenous dose of 5 mg/kg to rats, DMP 323
       exhibited an apparent volume of distribution at steady-state of 6.36
       liters/kg and clearance of 7.12 liters/hr/kg. The same dose administered
       intravenously to dogs resulted in apparent volume of distribution at
       steady-state and clearance values of 2.28 liters/kg and 1.48
       liters/hr/kg, respectively. Elimination half-lives were 0.95 hr in rats
       and 1.80 hr in dogs. DMP 323 was rapidly absorbed from oral solution
       doses in rats (3, 5, and 10 mg/kg) and dogs (5 and 10 mg/kg), achieving
       maximum plasma concentrations in 1 hr or less in both species. Absolute
       bioavailability of DMP 323 from oral doses ranged from 15 to 27% in rats
       and from 37 to 38% in dogs. Pharmacokinetics were unchanged in rats and
       dogs over 8-day t.i.d. and 5-day b.i.d. multiple oral dose regimens,
       respectively. Oral doses administered to fed animals resulted in lower
       plasma concentrations of DMP 323 than the same doses administered to
       fasted animals. Because of its in vitro high potency and acceptable
       pharmacokinetics, DMP 323 seems to be a worthy candidate for further
       study in the effort to develop an inhibitor of HIV protease for use in
       the therapy of AIDS.
 DE    Administration, Oral  Animal  Biological Availability  Comparative Study
       Dogs  Half-Life  HIV Protease Inhibitors/BLOOD/*PHARMACOKINETICS
       Injections, Intravenous  Male  Rats  Rats, Sprague-Dawley  Species
       Specificity  Urea/*ANALOGS & DERIVATIVES/BLOOD/PHARMACOKINETICS  JOURNAL
       ARTICLE

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