In vivo and in vitro myocardial binding of risperidone and 9-hydroxyrisperidone

Antipsychotic drugs have been found to prolong the QT interval, a phenomenon that, when severe, may facilitate the occurrence of complex ventricular arrhythmia such as torsade de pointes. Concentration-dependent QT prolongation has been demonstrated in vitro with such recent drugs as risperidone on Purkinje fibers and in isolated feline hearts. In vivo, there appears to be a relationship between plasma levels and QTc prolongation. This study was designed to estimate cardiac levels in vivo during treatment. For that purpose, we examined both in vivo and in vitro the ratio between plasma and cardiac tissue concentrations of risperidone and its active metabolite 9-hydroxyrisperidone. Binding parameters for different concentrations were determined in vitro by equilibrium dialysis. In vivo, they were determined by intraperitoneal administration of three doses in the guinea pig. Drug concentrations were determined by a high-performance liquid chromatography method with UV detection developed for that purpose. For risperidone, plasma protein binding varied from 67 to 43% and cardiac homogenate binding varied from 90 to 78%. 9-Hydroxyrisperidone values were lower. Tissue levels were 4.5-fold higher than plasma levels. Binding parameters were similar both in vivo and in vitro. From this model, the relevance of in vitro electrophysiological studies to clinical plasma concentrations can be approached.