Rp. Kapil et Gn. Lam, DOSE-DEPENDENT AND SPECIES-DEPENDENT PHARMACOKINETICS OF A NOVEL SIGMA-RECEPTOR ANTAGONIST, DUP-734, Research communications in molecular pathology and pharmacology, 88(1), 1995, pp. 3-20
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.