title: Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man.
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 l/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 greater than 5% of plasma radioactivity.
authors.affiliation: Department of Drug Metabolism, Pfizer Central Research, Kent, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Smith
authors.forename: H S
authors.initials: HS
authors.lastname: Rasmussen
authors.forename: D A
authors.initials: DA
authors.lastname: Stopher
authors.forename: D K
authors.initials: DK
authors.lastname: Walker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D010627:Phenethylamines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide