A dose‐ranging study of UK‐68,798, a novel class III anti‐arrhythmic agent, in normal volunteers.

Gemmill, J D; Howie, Catherine A.; Modesti, Pietro Amedeo; Kelman, Andrew W.; Rasmussen, H. S.; Hillis, W. S.; Elliott, HL

doi:10.1111/j.1365-2125.1991.tb03926.x

Cited by 28 publications

(15 citation statements)

References 9 publications

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“…T o date, information on the pharmacokinetics of dofetilide is limited to that obtained in man after intravenous administration (Sedgewick et al 1991, Gemmill et al 1991. In these studies the compound exhibited linear kinetics with mean plasma clearances of 4.7 and 5.2 ml/min per kg and mean terminal half-lives of 9.7 and 8.1 h. This paper reports the pharmacokinetics and metabolism in animals and man.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

et al. 1992

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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.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

et al. 1992

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“…The present study was, therefore, designed to answer the question of whether dofetilide, at a clinically relevant concentration [14,15], lengthens the actionpotential duration in the hyperkalemic zone as it does in the normokalemic zone in myocardium at various pacing frequencies. The electrophysiological effects of dofetilide were examined when both [K ÷ ]o and pacing cycle length were altered in isolated guinea-pig ventricular papillary muscle.…”

mentioning

confidence: 99%

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle

Yang

Tande

Lathrop

et al. 1992

Cardiovasc Drug Ther

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The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). These changes were accompanied by a small shortening of APD90, but with an increase in ERP; i.e., the ERP/APD90 ratio was increased. Dofetilide also significantly lengthened APD90 at 10 mM [K+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.

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“…57,58 In clinical trials, dofetilide produced a dose-dependent effect on myocardial repolarization, as shown by a significant prolongation of the QTc interval duration on ECG. 59,60 Dofetilide does not alter the PR or QRS intervals, a finding that supports its lack of effect on conduction velocity. 61 With long-term dosing, the maximum prolongation of the QTc interval usually occurs 48 hours after start of therapy, indicating that proarrhythmic adverse effects are most likely to occur within this period.…”

Section: Dofetilidementioning

confidence: 78%

“…76 Peak plasma concentrations are typically reached within 3 hours after administration. 59,61 Plasma protein binding is estimated at 60-70%, with a volume of distribution approximately 3 L/kg. 59 Dofetilide follows a linear first-order kinetics model.…”

Section: Dofetilidementioning

confidence: 99%

A Review of Class III Antiarrhythmic Agents for Atrial Fibrillation: Maintenance of Normal Sinus Rhythm

Tsikouris

Cox

2001

Pharmacotherapy

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A noteworthy shift from class I to class III antiarrhythmic agents for suppression of atrial fibrillation has occurred. Sotalol, amiodarone, and dofetilide have been evaluated for their ability to maintain sinus rhythm in patients with chronic atrial fibrillation. All of these agents are moderately effective; however, amiodarone appears to be most efficacious. Aside from their common class III actions, these agents have profoundly different pharmacologic, pharmacokinetic, safety, and drug interaction profiles that help guide drug selection. Amiodarone and dofetilide are safe in patients who have had a myocardial infarction and those with heart failure. The safety of commercially available d,l-sotalol in these patients is poorly understood. Torsades de pointes is the most serious adverse effect of sotalol and dofetilide, and risk increases with renal dysfunction. Amiodarone has minimal proarrhythmic risk but has numerous noncardiac toxicities that require frequent monitoring. Overall, an ideal antiarrhythmic agent does not exist, and drug selection should be highly individualized.

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A dose‐ranging study of UK‐68,798, a novel class III anti‐arrhythmic agent, in normal volunteers.

Abstract: (245 1) were found to be independent of dose with low levels of intra-and inter-patient variability. 4 UK-68,798 has electrophysiological effects indicative of selective class III antiarrhythmic activity and merits further assessment in clinical studies.

Cited by 28 publications

References 9 publications

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle

A Review of Class III Antiarrhythmic Agents for Atrial Fibrillation: Maintenance of Normal Sinus Rhythm

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