Abstract
1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide.
2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism.
3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2˙8–6˙3***1/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0˙32, male rat 0˙5 and female rat 1˙2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4˙6 and 7˙6 h respectively).
4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present.
5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide.
6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for >5% of plasma radioactivity.