DOSE-DEPENDENT AND SPECIES-DEPENDENT PHARMACOKINETICS OF A NOVEL SIGMA-RECEPTOR ANTAGONIST, DUP-734

The pharmacokinetics of a novel sigma receptor antagonist, DuP 734, wa s evaluated in mice, rats, beagle dogs and cynomolgus monkeys at vario us intravenous and oral doses utilizing a specific reversed-phase HPLC assay. Following intravenous dosing, the disposition of DuP 734 in al l species was characterized by high total body systemic plasma clearan ce (46 to 87 ml/min/kg) and large steady-state volume of distribution (3.6 to 6.8 l/kg). The terminal elimination half-life ranged from 50 t o 83 min. The gastrointestinal absorption from an aqueous solution was very rapid in mice and rats with peak DuP 734 plasma concentrations a ttained within 5 and 20 min following administration, respectively. Th e peak plasma concentrations in dogs and monkeys were attained within 35 and 130 min, respectively. The absolute bioavailability in mice ran ged from 29 to 46% at doses of 3.1 to 30.1 mg/kg. The bioavailability increased from 4 to 10% and from 14 to 72% when doses were increased f rom 12.5 to 50 mg/kg and 1 to 3 mg/kg of DuP 734 in rats and dogs, res pectively. The bioavailability in monkeys was 30.5% at 9.3 mg/kg DuP 7 34 dose. The dose dependent pharmacokinetics of DuP 734 was observed w ithin narrow dose ranges in ail animal species investigated.