During long-term treatment with psychotropic drugs both direct and indirect interactions between those drugs and cytochrome P450 (CYP) isoforms are possible. The direct interactions relying on the binding of the parent drugs to the catalytic site of enzyme (or in its vicinity) are characteristic of substrates and/or classical inhibitors and are easily observed in vitro. Antidepressants and neuroleptics are substrates of many CYP-isoforms, being metabolized by them to different products. CYP2D6 is an isoform of great importance to the metabolism of psychotropics, being mainly involved in catalyzing hydroxylation reactions. Other CYP-isoforms (CYP1A2, CYP2C19, CYP3A4) are involved in N-demethylation and ring-sulphoxidation pathways. Some of psychotropic drugs and their stable metabolites (e.g. desipramine, nortriptyline, norfluoxetine) are capable of directly and reversibly inhibiting some CYP-isoforms, mainly CYP2D (SSRIs, TADs, phenothiazines), less frequently CYP3A4 (nefazodone) and CYP1A2 (fluvoxamine, perazine), and less potently CYP2C (fluoxetine, nefazodone, levomepromazine). Indirect interactions via forming CYP-drug reactive metabolite complexes require a longer presence of drug in the environment of enzyme. Many psychotropic drugs (TADs, SSRIs, phenothiazines) are capable of producing reactive/intermediate metabolites which form inhibitory complexes with CYP-isoforms. In contrast to parent compounds or their stable (pharmacologically acting) N-demethylated metabolites, the binding of CYP with reactive/intermediate metabolites is irreversible in vivo. However, it takes a few days or weeks for a drug in the living organism to influence the expression of genes coding for CYP or CYP-regulating receptors. As drugs acting on the central nervous system (CNS) and displaying many different pharmacological mechanisms, psychotropics may affect physiological regulation of CYP expression via CNS-dependent endocrine and immune systems. Psychotropics may also influence the metabolism of endogenous substances important for enzyme regulation. It is also not excluded that they are able to act as exogenous ligands of nuclear receptors involved in the regulation of the transcription of genes coding for CYP. Induction of rat CYP2C6 (imipramine, SSRIs, mirtazapine), CYP2C11 (desipramine, fluoxetine) and CYP3A (sertraline and risperidone) or inhibition of CYP2C11 and CYP3A (levomepromazine, perazine, thioridazine), produced by chronic treatment only was observed. Direct and indirect interactions between psychotropic drugs and cytochrome P450 overlap during prolonged treatment, which may have an impact on the metabolism of not only a psychotropic drug producing an interaction, but also of other simultaneously administrated drugs and physiologically important endogenous substances.

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