The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions

The purpose of the present study was to investigate the contribution of lys osomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepr essants (imipramine, amitriptyline) or selective serotonin reuptake inhibit ors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slic es of various rat tissues as a system with intact lysosomes. Thioridazine a nd antidepressants (5 mu M) were incubated separately or jointly with the t issue slices in the absence or presence of "lysosomal inhibitors," i.e., am monium chloride or monensin. The results show that the contribution of lyso somal trapping to the total tissue uptake of thioridazine is as important a s phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive i nteractions between thioridazine and the investigated antidepressants at th e level of cellular distribution. Thioridazine and the antidepressants, bot h tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of l ysosomal inhibitors. In general, the observed interactions between thiorida zine and antidepressants occurred only in those tissues in which thioridazi ne showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) b ut were not observed in the presence of ammonium chloride. The above findin g provides evidence that the interactions proceeded at the level of lysosom al trapping. In the adipose tissue and heart no lysosomal trapping of thior idazine was detected and those tissues were not the site of such an interac tion. Since the organs and tissues involved in the distributive interaction s constitute a major part of the organism and take up most of the total dru g in the body, the interactions occurring in them may cause a substantial s hift of the drugs to organs and tissues poor in lysosomes, e.g. the heart a nd muscles. An in vivo study into the thioridazine-imipramine interaction s howed that joint administration of the drugs under study (10 mg/kg ip) incr eased drug concentration ratios of lysosome-poor tissue/plasma and lysosome -poor/lysosome-rich tissue. Considering serious side effects of thioridazin e and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine-antidepressant combinations studied should be approached with respect to the appropriate dose adjustment. (C) 1999 Academic Press.