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  2. In vitro preclinical cardiac assessment of tolterodine and terodiline: multiple factors predict the clinical experience

In vitro preclinical cardiac assessment of tolterodine and terodiline: multiple factors predict the clinical experience

  • J Cardiovasc Pharmacol. 2006 Nov;48(5):199-206. doi: 10.1097/01.fjc.0000246853.15926.d4.
Ruth L Martin 1 Zhi Su James T Limberis Jason D Palmatier Marlon D Cowart Bryan F Cox Gary A Gintant
Affiliations

Affiliation

  • 1 Department of Integrative Pharmacology, Abbott, Abbott Park, Illinois 60064-6119, USA. ruth.martin@abbott.com
Abstract

Terodiline and tolterodine are drugs used to treat urinary incontinence. Terodiline was removed from the market in 1991 for proarrhythmia, whereas tolterodine has a generally benign clinical cardiac profile. To assess differences in the electrophysiologic actions of these drugs, we evaluated their effects on hERG current (HEK cells) and cardiac Purkinje fiber repolarization. The IC50 for hERG block (37 degrees C) by tolterodine was 9.6 nM and by terodiline was 375 nM, values near or below clinical concentrations. Tolterodine elicited concentration-dependent prolongation of the action potential duration (APD90). In contrast, terodiline depressed the action potential plateau and induced triangulation without affecting APD90. The triangulation ratios (normalized ratio of APD50 over APD90) for terodiline were 0.94 and 0.59 for 1.0 and 10 microM and for tolterodine, were 0.99 and 0.97 at 7 and 70 nM. In summary, tolterodine, a potent hERG blocker, has a benign clinical cardiac profile at therapeutic concentrations that may be due to its lack of triangulation, as well as extensive plasma protein binding. However, at supratherapeutic concentrations, preclinical data predict risk of QT prolongation. These data suggest that hERG block and triangulation are among multiple factors that must be considered in preclinical cardiac safety assessments.

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