Tolerance to the repolarization effects of rac-sotalol during long-term treatment

Br J Clin Pharmacol. 1997 Nov;44(5):463-70. doi: 10.1046/j.1365-2125.1997.t01-1-00604.x.


Aims: To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol.

Methods: The effect of rac-sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6-day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure beta-adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship.

Results: In all patients QT interval prolongation was linearly correlated with rac-sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1+/-6.3% vs +14.2+/-3.3%; peak concentration: 1.64+/-0.49 mg l(-1) vs 1.83+/-0.66 mg l(-1)). Line slopes were also unchanged following chronic treatment (21.8+/-8.9 vs 21.1+/-9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term beta-adrenoceptor blockade and tolerance development.

Conclusions: During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Administration, Oral
  • Adolescent
  • Adrenergic beta-Antagonists / pharmacokinetics
  • Adrenergic beta-Antagonists / therapeutic use*
  • Adult
  • Aged
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / therapeutic use*
  • Arrhythmias, Cardiac / drug therapy*
  • Drug Administration Schedule
  • Electrocardiography / drug effects
  • Female
  • Heart / drug effects
  • Heart / physiopathology*
  • Heart Rate / drug effects
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Propranolol / pharmacology
  • Sotalol / pharmacokinetics
  • Sotalol / therapeutic use*
  • Stereoisomerism


  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • Propranolol
  • Sotalol