Use of arterially perfused rabbit ventricular wedge in predicting arrhythmogenic potentials of drugs.
BACKGROUND
A growing number of drugs have reportedly been associated with delayed ventricular repolarization and a potentially fatal but rare arrhythmia, torsade de pointes (TdP). There is obviously a call for a validated proarrhythmia model that distinguishes proarrhythmic drugs from nonarrhythmogenic drugs.


METHODS
In this article, we validated the arterially perfused rabbit left ventricular wedge preparation model and examined its use in predicting proarrhythmic potentials of drugs. A fairly detailed methodological description about this technically challenging model was given, aiming to help others establish the assay successfully. Parameters commonly used in the action potential studies were verified and critical experimental conditions (e.g. stability and reproducibility of recordings) were examined. Six commercially available compounds with various proarrhythmic potentials were administered in the model to evaluate their correlations with individual clinical outcomes.


RESULTS
Our study indicated that, in a successful experiment, the action potential duration (APD) can be stably maintained for several hours without intervention. Dofetilide, DL-sotalol, cisapride, risperidone and moxifloxacin increased endo- and epicardial APD(90), QT interval and T(P-E) (peak-to-end time of the T wave) in a reverse use-dependent manner within clinically relevant concentration ranges. Phase 2 early afterdepolarizations (EADs) were observed at 1.6, 2.3, 16.7, 37.5 and 7.9 fold, respectively, their corresponding unbound therapeutic concentrations. In contrast, fluoxetine at up to 3 microM (approximately 35 fold unbound therapeutic mean plasma concentration after 60 mg/day, p.o. for 5 weeks) had only a mild prolonging effect on APD(90) and QT with essentially no effect on T(P-E).


CONCLUSIONS
Our results strongly support the usefulness of this model in predicting a compound's arrhythmogenic potential in humans within clinically relevant concentration ranges, and the experimental results with this model need to be interpreted in light of each drug's pharmacokinetic and pharmacodynamic behavior in clinic.
Department of Safety Pharmacology, Worldwide Safety Sciences, Groton Laboratories, Pfizer Global Research and Development, Groton, CT 06340, USA.
Xian
X
Chen
Jason S
JS
Cordes
Jenifer A
JA
Bradley
Zhuoqian
Z
Sun
Jun
J
Zhou
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003331:Coronary Vessels; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D010477:Perfusion; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000503:physiopathology