Tolerance to the repolarization effects of ‘oorac‘ox-sotalol during long-term treatment
Article first published online: 2 OCT 2003
British Journal of Clinical Pharmacology
Volume 44, Issue 5, pages 463–470, November 1997
How to Cite
Padrini, R., Gusella, M., Al Bunni, M., Piovan, D., Zordan, R., Magnolfi, G., Maiolino, P. and Ferrari, M. (1997), Tolerance to the repolarization effects of ‘oorac‘ox-sotalol during long-term treatment. British Journal of Clinical Pharmacology, 44: 463–470. doi: 10.1046/j.1365-2125.1997.t01-1-00604.x
- Issue published online: 2 OCT 2003
- Article first published online: 2 OCT 2003
- Cited By
- QT interval;
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 &bgr;-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−1vs 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 &bgr;-adrenoceptor blockade and tolerance development.
Conclusions During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.