Pharmacokinetics of HIV protease inhibitor DMP 323 in rats and dogs.

Abstract	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.
Authors	M F Grubb, Y N Wong, D L Burcham, P L Saxton, C Y Quon, S M Huang
Journal	Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) 1994 Sep-Oct Vol. 22 Issue 5 Pg. 709-12 ISSN: 0090-9556 [Print] United States
PMID	7835221 (Publication Type: Comparative Study, Journal Article)
Chemical References	Azepines HIV Protease Inhibitors Urea DMP 323
Topics	Administration, Oral Animals Azepines Biological Availability Dogs HIV Protease Inhibitors (blood, pharmacokinetics) Half-Life Injections, Intravenous Male Rats Rats, Sprague-Dawley Species Specificity Urea (analogs & derivatives, blood, pharmacokinetics)

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