Dose and species dependent pharmacokinetics of a novel sigma receptor antagonist, DuP 734.
The pharmacokinetics of a novel sigma receptor antagonist, DuP 734, was evaluated in mice, rats, beagle dogs and cynomolgus monkeys at various intravenous and oral doses utilizing a specific reversed-phase HPLC assay. Following intravenous dosing, the disposition of DuP 734 in all species was characterized by high total body systemic plasma clearance (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 to 83 min. The gastrointestinal absorption from an aqueous solution was very rapid in mice and rats with peak DuP 734 plasma concentrations attained within 5 and 20 min following administration, respectively. The peak plasma concentrations in dogs and monkeys were attained within 45 and 130 min, respectively. The absolute bioavailability in mice ranged 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 from 12.5 to 50 mg/kg and 1 to 3 mg/kg of DuP 734 in rats and dogs, respectively. The bioavailability in monkeys was 30.5% at 9.3 mg/kg DuP 734 dose. The dose dependent pharmacokinetics of DuP 734 was observed within narrow dose ranges in all animal species investigated.
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Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA.
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D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013045:Species Specificity; D014018:Tissue Distribution
D010880:Piperidines; D017480:Receptors, sigma; D012702:Serotonin Antagonists; C078773:DuP 734