INTERACTIONS BETWEEN PROMAZINE AND ANTIDEPRESSANTS AT THE LEVEL OF CELLULAR-DISTRIBUTION

The pharmacokinetic interactions in clinical combinations of a phenoth iazine neuroleptic and antidepressants at the level of cellular distri bution were investigated. Uptake experiments were performed on slices of various rat tissues as a system with intact lysosomes. Promazine an d antidepressants (imipramine, amitriptyline, sertraline, fluoxetine) were incubated separately or jointly with tissue slices for 1 hr. Init ial concentration of each drug was 5 mu M. The interaction studies wer e carried out in the absence and presence of ammonium chloride (20 mM) , a lysosomotropic compound which increases the internal pH value of l ysosomes. All the tissues known for their abundance of lysosomes (the lungs, liver, kidneys) were the site of an interaction between promazi ne and antidepressants. The neuroleptic and antidepressants mutually i nhibited their tissue uptake. The potency of interference of each anti depressant with the lysosomal uptake of promazine was similar. The int eractions did not occur in the presence of ammonium chloride, which in dicates involvement of the lysosomal trapping. Carbamazepine, a lipoph ilic but non-lysosomotropic drug, did not interfere with the promazine uptake, and the adipose tissue containing very few lysosomes was neve r the site of interaction in our experiment. Distribution interactions were also observed in the brain and in some cases in muscles (the tis sues less abundant of lysosomes), the effect of the inhibitory drug be ing usually more potent than that of ammonium chloride. Most of the in teractions occurring in these two tissues were also observed in the pr esence of ammonium chloride, which suggests involvement, at least part ially of a non-lysosomal trapping mechanism. The consequences of the o bserved distributive interactions at the level of lysosomal trapping i n vitro are diminished intralysosomal concentration of the basic lipop hilic psychotropic and its increase in cell membranes and fluids. In v iva, a shift from the organs or tissues rich in lysosomes to those les s abundant in these organella, and an increase in the free drug concen tration in body fluids may be expected. In conclusion, the obtained re sults show that, regardless of the previously known metabolic interact ions between psychotropics, interactions at the levels of cellular and body distribution are also feasible.