The effect of new atypical antipsychotic drugs on the expression of transcription factors regulating cytochrome P450 enzymes in rat liver.

Background: Our recent studies showed that prolonged administration of novel atypical antipsychotics affected the expression and activity of cytochrome P450 (CYP), as demonstrated in vitro on human hepatocytes and in vivo on the rat liver. The aim of the present work was to study the effect of repeated treatment with asenapine, iloperidone, and lurasidone on the expression of transcription factors regulating CYP drug-metabolizing enzymes in rat liver.

Methods: The hepatic mRNA (qRT-PCR) and protein levels (Western blotting) of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPARγ) were measured in male Wistar rats after 2 week-treatment with asenapine, iloperidone or lurasidone.

The Novel Atypical Antipsychotic Lurasidone Affects Cytochrome P450 Expression in the Liver and Peripheral Blood Lymphocytes.

Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction.

The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats.

Background: Liver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is negatively regulated by the brain serotoninergic system.

The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain.

The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D.

The Atypical Antipsychotic Lurasidone Affects Brain but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schizophrenia.

The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg/kg ip.) for two weeks.

The impact of noradrenergic neurotoxin DSP-4 and noradrenaline transporter knockout (NET-KO) on the activity of liver cytochrome P450 3A (CYP3A) in male and female mice.

Background: Our earlier studies have shown that the brain noradrenergic system regulates cytochrome P450 (CYP) in rat liver via neuroendocrine mechanism. In the present work, a comparative study on the effect of intraperitoneal administration of the noradrenergic neurotoxin DSP-4 and the knockout of noradrenaline transporter (NET-KO) on the CYP3A in the liver of male and female mice was performed.

Methods: The experiments were conducted on C57BL/6J WT and NET male/female mice.

The mechanisms of interactions of psychotropic drugs with liver and brain cytochrome P450 and their significance for drug effect and drug-drug interactions.

Cytochrome P450 (CYP) plays an important role in psychopharmacology. While liver CYP enzymes are responsible for the biotransformation of psychotropic drugs, brain CYP enzymes are involved in the local metabolism of these drugs and endogenous neuroactive substances, such as neurosteroids, and in alternative pathways of neurotransmitter biosynthesis including dopamine and serotonin. Recent studies have revealed a relation between the brain nervous system and cytochrome P450, indicating that CYP enzymes metabolize endogenous neuroactive substances in the brain, while the brain nervous system is engaged in the central neuroendocrine and neuroimmune regulation of cytochrome P450 in the liver.

Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms.

enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (K = 11.

Cytochrome P450 2D (CYP2D) enzyme dysfunction associated with aging and serotonin deficiency in the brain and liver of female Dark Agouti rats.

Among the enzymes that support brain metabolism, cytochrome P450 (CYP) enzymes occupy an important place. These enzymes catalyze the biotransformation pathways of neuroactive endogenous substrates (neurosteroids, neurotransmitters) and are necessary for the detoxification processes. The aim of the present study was to assess changes in the CYP2D activity and protein level during the aging process and as a result of serotonin deficiency in the female brain.

The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver.

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip.

Chronic treatment with asenapine affects cytochrome P450 2D (CYP2D) in rat brain and liver. Pharmacological aspects.

Neuroleptics have to be used for a long time to produce a therapeutic effect. Cytochrome P450 2D (CYP2D) enzymes mediate alternative pathways of neurotransmitter synthesis (i.e.

The Effect of Chronic Iloperidone Treatment on Cytochrome P450 Expression and Activity in the Rat Liver: Involvement of Neuroendocrine Mechanisms.

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients' lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks.

The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms.

Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats.

Asenapine and iloperidone decrease the expression of major cytochrome P450 enzymes CYP1A2 and CYP3A4 in human hepatocytes. A significance for drug-drug interactions during combined therapy.

Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver.

Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4.

Background: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs.

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions.

Background: The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes).

Methods: The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4'-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1'-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC.

Results: Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (K = 0.

In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions.

Background: Inhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug-drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver.

Methods: The experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes).