Contribution of Lysosomal Trapping to the Total Tissue Uptake of Psychotropic Drugs

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Abstract
The present study was aimed at assessing individual contributions of the phospholipid binding and lysosomal trapping to the total tissue uptake of psychotropic drugs with different chemical structures, such as promazine, imipramine, amitriptyline, fluoxetine, sertraline (basic lipophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the pharmacokinetic 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 μM. The results were compared with those obtained in the presence of the "lysosomal inhibitors", ammonium chloride or monensin. The basic lipophilic psychotropics showed high uptake in tissues known for the abundance of lysosomes, mainly the lungs. The highest drug accumulation was found for promazine and amitriptyline. "Lysosomal inhibitors" significantly decreased the uptake of the basic lipophilic drugs, particularly in the lungs and liver. The most potent effect was observed 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 amitriptyline, imipramine and sertraline. The only exception to the above regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome‐rich tissues such as the lungs or liver. Carbamazepine did not show lysosomotropism. Amitriptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly. In the presence of ammonium chloride the interaction did not occur. In conclusion, the obtained results show that (1) the lysosomal trapping is an important factor determining the distribution of the basic lipophilic psychotropics; however (2) their tissue uptake depends more on the phospholipid binding than on the lysosomal trapping; (3) the lysosomal trapping may be involved in the pharmacokinetic interactions between psychotropics.