CONTRIBUTION OF LYSOSOMAL TRAPPING TO THE TOTAL TISSUE UPTAKE OF PSYCHOTROPIC-DRUGS

The present study was aimed at assessing individual contributions of t he phospholipid binding and lysosomal trapping to the total tissue upt ake of psychotropic drugs with different chemical structures, such as promazine, imipramine. amitriptyline, fluoxetine, sertraline (basic li pophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the p harmacokinetic interactions in clinical combinations of psychotropics. Uptake experiments were carried out on slices of various rat tissues as a system with intact lysosomes. Initial concentration of each drug was 5 mu M. The results were compared with those obtained in the prese nce of the ''lysosomal inhibitors'', ammonium chloride or monensin. Th e basic lipophilic psychotropics showed high uptake in tissues known f or the abundance of lysosomes, mainly the lungs. The highest drug accu mulation was;as found for promazine and amitriptyline. ''Lysosomal inh ibitors' significantly decreased the uptake of the basic lipophilic dr ugs, particularly in the lungs and liver. The most potent effect was o bserved for amitriptyline, imipramine and promazine, The brain showed moderate accumulation of basic lipophilic psychotropics and the effect of the ''lysosomal inhibitors'' was significant only in the case of a mitriptyline. imipramine and sertraline. The only exception to the abo ve regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome-rich tissues such a s the lungs or liver. Carbamazepine did nor show lysosomotropism. Amit riptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly In the presence of ammonium chl oride the interaction did not occur. In conclusion, the obtained resul ts show that (1) the lysosomal trapping is an important factor determi ning the distribution of the basic lipophilic psychotropics: however ( 2) their tissue uptake depends more on the phospholipid binding than o n the lysosomal trapping: (3) the lysosomal trapping may be involved i n the pharmacokinetic interactions between psychotropics.