Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.
Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.
Titier
Karine
K
Department of Pharmacology and Toxicology, EA-3676, IFR 99, University Victor Segalen, Bordeaux, France. karine.titier@pharmaco.u-bordeaux2.fr
Canal
Mireille
M
Déridet
Evelyne
E
Abouelfath
Abdelilah
A
Gromb
Sophie
S
Molimard
Mathieu
M
Moore
Nicholas
N
D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016757:Death, Sudden, Cardiac; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011237:Predictive Value of Tests; D014018:Tissue Distribution
D014150:Antipsychotic Agents