Abstract
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 ∼8 h in rats, ∼20 h in dogs, ∼27 h in monkeys, and ∼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.
Footnotes
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Send reprint requests to: Dr. Randy C. Dockens, Bristol-Myers Squibb Pharmaceutical Research Institute, Rt. 206 and Province Line Road, Princeton, NJ 08543-4000. E-mail:randy.dockens{at}bms.com
- Abbreviations used are::
- SD
- Sprague-Dawley
- BMS
- Bristol-Myers Squibb
- GI
- gastrointestinal
- MS
- mass spectrometry
- QC
- quality control
- TLC
- thin-layer chromatography (chromatographic)
- ODS
- octadecasilane
- MS/MS
- tandem mass spectroscopy
- AUC(INF)
- area under the plasma concentration-time curve from 0 to infinity
- Cmax
- maximum plasma concentration
- CLT
- total clearance
- VDss
- steady-state volume of distribution
- Received October 26, 1999.
- Accepted May 18, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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