Tolerance to the repolarization effects of rac-sotalol during long-term treatment.
OBJECTIVE
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.
Padrini
R
R
Department of Pharmacology, University of Padua, Padova, Italy.
Gusella
M
M
Al Bunni
M
M
Piovan
D
D
Zordan
R
R
Magnolfi
G
G
Maiolino
P
P
Ferrari
M
M
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011433:Propranolol / Q000494:pharmacology; D013015:Sotalol / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D011433:Propranolol; D013015:Sotalol