Distribution interactions between perazine and antidepressant drugs. In vivo studies

Perazine belongs to the most frequently chosen neuroleptics for a combination with antidepressants in the therapy of complex or "treatment-resistant" psychiatric illnesses. The aim of the present study was to investigate the effect of the distribution interaction between perazine and antidepressants in vivo. Experiments were carried out on male Wistar rats. Animals received perazine and an antidepressant drug (imipramine or fluoxetine), separately or jointly, at a dose of 10 mg/kg ip. Concentrations of perazine, imipramine, fluoxetine and their metabolites in the blood plasma and tissues were measured at 1 h after administration of the drugs (HPLC). Effects of distribution interactions were estimated on the basis of the calculated tissue/plasma and lysosome-poor/lysosome-rich tissue concentration ratios, considering the heart and muscles as lysosome-poor and the lungs, liver and kidneys as lysosome-rich ones. Both imipramine and fluoxetine diminished the tissue/plasma concentration ratios of perazine for the lungs and kidneys (not for the liver), but elevated those ratios for the brain, muscles and heart. On the other hand, perazine lowered the lungs/plasma concentration ratio of both antidepressants and the liver/plasma concentration ratio of imipramine. Simultaneously, perazine elevated the brain/plasma and heart/plasma concentration ratios of both antidepressants. Consequently, the perazine concentration ratios of lysosome-poor/lysosome-rich tissue significantly increased in the presence of the investigated antidepressants, with an exception of the muscles/liver concentration ratio. At the same time, perazine raised the heart/lysosome-rich tissue concentration ratios of imipramine and fluoxetine, not changing significantly the muscles/lysosome-rich concentration ratios of the antidepressants. In conclusion, the presented results provide evidence that the observed in vitro distributive interactions between perazine and the antidepressants occur also in vivo, leading to a shift of the drugs from organs rich in lysosomes to those poor in these organella, in particular to the heart. Perazine and the antidepressants mutually increased the drug concentration ratios of heart/plasma and heart/lysosome-rich tissue, i.e. the heart/lung, heart/liver and heart/kidneys ratios. Similar results were obtained with lysosome-poor muscles in the case ofperazine. Moreover, the obtained results indicate that, apart from the lysosome density in the investigated tissues, the potential metabolic interactions in the liver and the order of drug circulation in a body have an important impact on the calculated drug concentration ratios.