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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 pM. 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.

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Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non-specific binding to membrane phospholipids, and ion-trapping within acidic cellular compartments. The aim of this study was to assess the individual contributions of these two mechanisms on the uptake in vitro of desipramine and chloroquine into tissue slices of control and desipramine-treated rats. Drug uptake into intact slices was compared with uptake into slices with destroyed or non-functional acidic compartments. The sequence of desipramine uptake by tissue slices of eight different organs was: lungs > brain > heart > diaphragm > kidneys > skeletal muscles > adipose tissue > liver. The low desipramine concentration in liver may be due to metabolism of the parent drug by cytochrome P-450. Uptake of chloroquine differed widely between slices of different organs with the sequence: lungs > kidneys = brain = liver > diaphragm = heart = skeletal muscles > adipose tissue. Destruction or inactivation of the acidic compartments by homogenization and freeze-thawing or by ammonium chloride, sodium fluoride, or monensin, reduced drug uptake to similar extents. The reduction was organ-specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affected than that of desipramine, suggesting that ion-trapping is the main factor for chloroquine accumulation, while binding to membrane phospholipids, is the main factor for desipramine uptake. Single or multiple-dose treatments of rats with desipramine hardly had any effect on consecutive desipramine uptake into lung and liver slices, while the accumulation of chloroquine was enhanced in these slices. In conclusion, the extent of uptake of cationic amphiphilic drugs into tissue slices was tissue-specific, and the contribution of the two uptake mechanisms was strongly drug-dependent.

This paper reviews evidence that changes in the functioning of the brain dopaminergic system affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A in the case of the tuberoinfundibular pathway or CYP1A and CYP3A in the case of the mesolimbic pathway), as well as blood plasma concentration of the respective pituitary hormones in the rat. Thus, the brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds through the dopaminergic D(2) receptors of the pituitary (activated by the tuberoinfundibular pathway) and the D(2) receptors of the nucleus accumbens (activated by the mesolimbic pathway and conveying a message from the nucleus accumbens to the paraventricular nucleus of the hypothalamus). These receptors directly (GH) or indirectly (CRH --> ACTH --> corticosterone; TRH --> TSH --> T(3)) stimulate the secretion of hormones, which activate nuclear/cytosolic receptors controlling CYP genes. Thus, the prediction of neuroactive drug action on hepatic CYP and drug-drug interactions on the basis of in vitro studies only is not sufficient, because such an experimental model does not allow the central neuroendocrine regulation of the enzyme.

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A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT 6 receptor ligands. The study allowed for the identification of 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a potent and selective 5-HT 6 receptor antagonist. The selected compound, was evaluated in vivo in a novel object recognition (NOR) and forced swim (FST) tests in rats, demonstrating distinct pro-cognitive and antidepressant-like properties (MED = 1 mg/kg and 0.1 mg/kg, i.p., respectively). Compound SB-742457, used as comparator, reversed memory deficits in NOR task in similar doses, while in FST it was active in 10−30-fold higher dose (3 mg/kg). In contrast to SB-742457, which was active in Vogel test (MED = 3 mg/kg), compound 25 displayed no anxiolytic activity.