Domperidone should not be considered a no-risk alternative to cisapride in the 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. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia.


RESULTS
Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use-dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from 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) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go-related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated 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 similar 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 Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.
Drolet
B
B
Institut de cardiologie de Québec, Hôpital Laval, Facultés de Pharmacie, Université Laval, Sainte-Foy, Québec, Canada.
Rousseau
G
G
Daleau
P
P
Cardinal
R
R
Turgeon
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000932:Antiemetics / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016466:CHO Cells; D002304:Cardiac Pacing, Artificial; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D020117:Cisapride / Q000627:therapeutic use*; D006224:Cricetinae; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; D004294:Domperidone / Q000009:adverse effects*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D018570:Risk Assessment; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection
D000932:Antiemetics; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D004294:Domperidone; D020117:Cisapride