Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions.

Distribution of a drug in the body is dependent on its permeation properties, the blood flow rates in various tissues, and on plasma and tissue uptake. The distribution of drugs in vivo is largely determined by uptake competitions between blood and tissues, as well as competitions among individual tissues. Basic lipophilic drugs are characterized by extensive accumulation in tissues, which leads to a high volume of distribution. Nonspecific binding to cellular membranes and uptake by acidic compartments (mainly lysosomes) are responsible for such a distribution pattern. Lysosomal trapping is an important mechanism of distribution of basic psychotropic drugs; however, the tissue distribution of the aliphatic-type phenothiazine neuroleptic promazine, tricyclic antidepressants (TADs) and selective serotonin reuptake inhibitors (SSRIs) depends more on phospholipid binding than on lysosomal trapping, whereas in the case thioridazine and perazine, lysosomal trapping is as important for the tissue uptake as is phospholipid binding. Neuroleptics and antidepressants mutually inhibit their lysosomal uptake. A decrease in the intralysosomal drug concentrations in vivo leads to a shift of the drug from organs abundant in lysosomes (lungs, liver and kidneys) to those poor in these organella, e.g., the heart, which may be of clinical importance (cardiotoxicity). The brain is not a homogenous organ, i.e., the phospholipid pattern and density of lysosomes vary in its different regions. Therefore, the contribution of the two mechanisms (lysosomal trapping and tissue binding) to total drug uptake is different in areas of the brain. Both lysosomal trapping and binding to cellular elements for psychotropics are higher in the grey matter and neurons than in the white matter and astrocytes, respectively. Lysosomal trapping and distribution interactions of psychotropics take place mainly in neurons. A decrease (via a distributive interaction) in the concentration of psychotropics in lysosomes (depot) may lead to an increase in their level in membranes and tissue fluids (i.e., in concentrations and compartments relevant to their pharmacological action) and, in consequence, to enhancement of the drug binding to neurotransmitter receptors and/or transporters.