Perazine, a
piperazine-type
phenothiazine neuroleptic, is the most frequently chosen
drug for combination with
antidepressants in the
therapy of complex or 'treatment-resistant'
psychiatric illnesses. The aim of the present study 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 distinguish between lysosomal trapping and tissue binding, the experiments were performed in the absence or presence of 'lysosomal inhibitors', i.e. the lysosomotropic compound
ammonium chloride or [H+]
ionophore monensin, which abolish the pH-gradient of lysosomes. Under steady-state conditions, the highest tissue uptake of
perazine was observed for the adipose tissue, which descended in the following order: the adipose tissue>lungs>liver>heart=brain>kidneys>muscles. The contribution of lysosomal trapping to the total 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 tissue, no lysosomotropism of
perazine was observed. Of the psychotropics studied,
perazine was the only
drug showing such a high degree of lysosomal trapping in muscles and distinct lysosomotropic properties in the heart.
Perazine and the
antidepressants used, both tricyclic (
imipramine,
amitriptyline) and
selective serotonin reuptake inhibitors (
fluoxetine,
sertraline), mutually decreased their tissue uptake. The potency of
imipramine to decrease
perazine uptake was similar to that of the 'lysosomal inhibitors'. Other
antidepressants seemed to exert a somewhat weaker effect. The above interactions between
perazine and
antidepressants were not observed in the presence of
ammonium chloride, which indicates that they proceeded at the level of lysosomal trapping. The adipose tissue in which the
drug uptake was not affected by the 'lysosomal inhibitors' was not the site of such an interaction.
Ammonium 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 antidepressants 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 in the concentration in vivo of the
neuroleptic and
antidepressants at the site of action, which, in turn, may increase the risk of cardiotoxic and
anticholinergic side-effects of
tricyclic antidepressants and
sedative and extrapyramidal effects of the
neuroleptic.