Lysosomal trapping as an important mechanism involved in the cellular distribution of perazine and in pharmacokinetic interaction with antidepressants

Perazine, a piperazine-type phenothiazine neuroleptic, is the most frequent ly chosen drug for combination with antidepressants in the therapy of compl ex or 'treatment-resistant' psychiatric illnesses. The aim of the present s tudy was to investigate the contribution of lysosomal trapping to the total tissue uptake of perazine, and the pharmacokinetic interaction between the neuroleptic and antidepressants. Experiments were carried out on slices of different rat organs regarded as a system with functional lysosomes. To di stinguish between lysosomal trapping and tissue binding, the experiments we re per formed in the absence or presence of 'lysosomal inhibitors', i.e. th e lysosomotrapic compound ammonium chloride or [H+] ionophore monensin, whi ch abolish the pH-gradient of lysosomes. Under steady-state conditions, the highest tissue uptake of perazine was observed for the adipose tissue, whi ch descended in the following order: the adipose tissue>lungs>liver>heart = brain >kidneys> muscles. The contribution of lysosomal trapping to the tot al tissue uptake amounted to about 40% in the liver, brain and muscles, to 30% in the kidneys, and to 25% in the heart and lungs. In the adipose tissu e, no lysosomotropism of perazine was observed. Of the psychotropics studie d, perazine was the only drug showing such a high degree of lysosomal trapp ing in muscles and distinct lysosomotropic properties in the heart. Perazin e and the antidepressants used, both tricyclic (imipramine, amitriptyline) and selective serotonin reuptake inhibitors (fluoxetine, sertraline), mutua lly decreased their tissue uptake. The potency of imipramine to decrease pe razine uptake was similar to that of the 'lysosomal inhibitors'. Other anti depressants seemed to exert a somewhat weaker effect. The above interaction s between perazine and antidepressants were not observed in the presence of ammonium chloride, which indicates that they proceeded at the level of lys osomal trapping. The adipose tissue in which the drug uptake was not affect ed by the 'lysosomal inhibitors' was not the site of such an interaction. A mmonium chloride did not affect the drug metabolism in liver slices; other tissues displayed only a negligible biotransformation of the psychotropics studied. A parallel metabolic interaction between perazine and tricyclic an tidepressants took part in liver slices (i.e. perazine and antidepressants mutually inhibited their metabolic pathways), but the influence of such an interaction on the lysosomal uptake of the parent compounds in liver slices did not seem to be great. A substantial decrease in concentrations of the drugs in lysosomes (depot form) observed in vitro may lead to an increase i n the concentration in vivo of the neuroleptic and antidepressants at the s ite of action, which, in turn, may increase the risk of cardiotoxic and ant icholinergic side-effects of tricyclic antidepressants and sedative and ext rapyramidal effects of the neuroleptic. (C) 1999 Elsevier Science B.V. All rights reserved.