Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.
Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.
Dockens
R C
RC
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA. randy.dockens@bms.com
Santone
K S
KS
Mitroka
J G
JG
Morrison
R A
RA
Jemal
M
M
Greene
D S
DS
Barbhaiya
R H
RH
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D001826:Body Fluids / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002522:Chlorocebus aethiops; D018592:Cross-Over Studies; D004285:Dogs; D006801:Humans; D008297:Male; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013997:Time Factors; D014018:Tissue Distribution
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; C078904:ifetroban