Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping

Abstract

1 Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its dierent regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2 Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of`lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na + /H + -ionophore monensin (10 mM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 mM. 3 Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline,¯uoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4 Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5 A dierential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6 A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue¯uids, may intensify the pharmacological action of the combined drugs.

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

“…The weaker signal in the GS2 tumor versus the healthy brain as well as the higher variability in distribution within the tumor compared with the U87 tumor may be explained by differences in tumor vascularization, which could impact GNE-317 distribution. Images suggest also different compound levels in white versus gray matter as previously reported with brain penetrant compounds (Daniel et al, 2001;Li et al, 2009).…”

Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

“…Monensin is routinely used in the cattle and a Vesicular to cytosolic concentration ratio ϭ (1 ϩ 10 pKa Ϫ pHv)/(1 ϩ 10 pKa Ϫ pHi) (Myers et al, 1995), where pHi Ϸ 7.27 is the assumed cytosolic pH (Le Couteur et al, 1993), pHv Ϸ 4.4 is the assumed lysosomal pH (Daniel et al, 2001) and pHv Ϸ 6.67 is the assumed mitochondrial pH in the fasted state (Pietri et al, 2001).…”

“…A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al, 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al, 1999). Lysosomal trapping of basic lipophilic drugs has also been demonstrated to be an important determinant of disposition for desipramine and chloroquine and psychotropic compounds such as the piperidine and piperazine-type neuroleptics (Daniel et al, 2001). The lysosomotropic properties of basic drugs are particularly important determining drug disposition and pharmacokinetics in lysosome-rich organs such as lungs, kidneys, or the liver.…”

Specific Effects of Antipsychotic Chlorpromazine on Glutamatergic Ionotropic Mechanisms. Novel Targets for Treatment Schizophrenia

“…This compound (Na + /H + -ionophore) is commonly recognized as fast and efficient lysosomal inhibitor [17,18]. We have suggested that ammonium chloride reduces the high lipophilicity of CPZ and prevents deterioration NMDAR functions.…”

“…This compound (Na + /H + -ionophore) is commonly recognized as fast and efficient lysosomal inhibitor [18]. Lysosomal trapping is an important mechanism of cellular and body distribution of basic psychotropic drugs, such as phenothiazine neuroleptics [19].…”