In vitro preclinical cardiac assessment of tolterodine and terodiline: multiple factors predict the clinical experience.
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.
Martin
Ruth L
RL
Department of Integrative Pharmacology, Abbott, Abbott Park, Illinois 60064-6119, USA. ruth.martin@abbott.com
Su
Zhi
Z
Limberis
James T
JT
Palmatier
Jason D
JD
Cowart
Marlon D
MD
Cox
Bryan F
BF
Gintant
Gary A
GA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002082:Butylamines / Q000494:pharmacology*; D002460:Cell Line; D003408:Cresols / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D010665:Phenylpropanolamine / Q000494:pharmacology*; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D002082:Butylamines; D003408:Cresols; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C010637:terodiline