Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans

Ifetroban is a potent and selective thromboxane receptor antagonist. This s tudy was conducted to characterize the pharmacokinetics, absolute bioavaila bility, and disposition of ifetroban after i.v. and oral administrations of [C-14]ifetroban or [H-3]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monke ys (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 similar to 8 h in rats, similar to 20 h in dogs, similar to 27 h in monkeys, and similar to 22 h in humans. Based on the steady-state volume of distribution, the d rug was extensively distributed in tissues. Absolute bioavailability was 25 , 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal e xcretion 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, urina ry 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 meta bolite at the C-14 position being the major metabolite observed in rat bile . Ifetroban was extensively metabolized after oral administration. Approxim ately 40 to 50% of the radioactivity in rat and dog plasma was accounted fo r by parent drug whereas, in humans, approximately 60% of the plasma radioa ctivity was accounted for by ifetroban acylglucuronide.