Domperidone should not be considered a no-risk alternative to cisapride inthe treatment of gastrointestinal motility disorders

Background-Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Alt hough electrolyte disturbances such as hypokalemia could account for some o f these events, we hypothesized that domperidone may have unsuspected elect rophysiological effects predisposing some patients to proarrhythmia. Methods and Results-Studies were undertaken in 9 isolated guinea pig hearts , which demonstrated reverse use-dependent prolongation of cardiac repolari zation by 100 nmol/L domperidone. Action potential duration increased 27% f rom baseline with domperidone (from 114+/-3 to 145+/-2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97+/-2 to 106+/-3 ms) wa s seen with pacing at a cycle length of 150 ms. Experiments in human ether- a-go-related gene (HERG)-transfected Chinese hamster ovary cells (n=32) dem onstrated a concentration-dependent block of the rapid component (I-Kr) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. Conclusions-Domperidone possesses cardiac electrophysiological effects simi lar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.