Interactions between promazine and antidepressants at the level of cellular distribution.
The pharmacokinetic interactions in clinical combinations of a phenothiazine neuroleptic and antidepressants at the level of cellular distribution were investigated. Uptake experiments were performed on slices of various rat tissues as a system with intact lysosomes. Promazine and antidepressants (imipramine, amitriptyline, sertraline, fluoxetine) were incubated separately or jointly with tissue slices for 1 hr. Initial concentration of each drug was 5 microM. The interaction studies were carried out in the absence and presence of ammonium chloride (20 mM), a lysosomotropic compound which increases the internal pH value of lysosomes. All the tissues known for their abundance of lysosomes (the lungs, liver, kidneys) were the site of an interaction between promazine and antidepressants. The neuroleptic and antidepressants mutually inhibited their tissue uptake. The potency of interference of each antidepressant with the lysosomal uptake of promazine was similar. The interactions did not occur in the presence of ammonium chloride, which indicates involvement of the lysosomal trapping. Carbamazepine, a lipophilic but non-lysosomotropic drug, did not interfere with the promazine uptake, and the adipose tissue containing very few lysosomes was never the site of interaction in our experiment. Distribution interactions were also observed in the brain and in some cases in muscles (the tissues less abundant of lysosomes), the effect of the inhibitory drug being usually more potent than that of ammonium chloride. Most of the interactions occurring in these two tissues were also observed in the presence of ammonium chloride. Most of the interactions occurring in these two tissues were also observed in the presence of ammonium chloride, which suggests involvement, at least partially, of a non-lysosomal trapping mechanism. The consequences of the observed distributive interactions at the level of lysosomal trapping in vitro are diminished intralysosomal concentration of the basic lipophilic psychotropic and its increase in cell membranes and fluids. In vivo, a shift from the organs or tissues rich in lysosomes to those less abundant in these organella, and an increase in the free drug concentration in body fluids may be expected. In conclusion, the obtained results show that, regardless of the previously known metabolic interactions between psychotropics, interactions at the levels of cellular and body distribution are also feasible.
Daniel
W A
WA
Polish Academy of Sciences, Institute of Pharmacology, Kraków, Poland.
Wójcikowski
J
J
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007099:Imipramine / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011395:Promazine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020280:Sertraline
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D005473:Fluoxetine; D000643:Ammonium Chloride; D000639:Amitriptyline; D002220:Carbamazepine; D015057:1-Naphthylamine; D011395:Promazine; D007099:Imipramine; D020280:Sertraline