PHARMACOKINETICS OF HIV PROTEASE INHIBITOR DMP-323 IN RATS AND DOGS

DMP 323 is a symmetrically substituted cyclic urea compound with demon strated activity against human immunodeficiency virus (HIV) in vitro. DMP 323 has been measured in rat and dog plasma via liquid-liquid extr action and HPLC. The limit of quantitation is 10 ng/ml using 0.5 ml pl asma. Following an intravenous dose of 5 mg/kg to rats, DMP 323 exhibi ted 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 intr avenously to dogs resulted in apparent volume of distribution at stead y-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 pla sma concentrations in 1 hr or less in both species. Absolute bioavaila bility of DMP 323 from oral doses ranged from 15 to 27% in rats and fr om 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, respe ctively. Oral doses administered to fed animals resulted in lower plas ma concentrations of DMP 323 than the same doses administered to faste d animals. Because of its in vitro high potency and acceptable pharmac okinetics, 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 the rapy of AIDS.