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 activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1'-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of CYP2D1 without affecting that of CYP2D2, CYP2D3, CYP2D4, and CYP2D5. In conclusion, lurasidone regulates brain (but not liver) CYP2D activity/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures.

Self microemulsifying drug delivery system of lurasidone hydrochloride for enhanced oral bioavailability by lymphatic targeting: In vitro, Caco-2 cell line and in vivo evaluation.

The global aim of this research was to develop and evaluate self-microemulsifying drug delivery system (SMEDDS) to improve oral bioavailability of Lurasidone Hydrochloride (LH). A chylomicron flow blocking approach was used to evaluate lymphatic drug transport. The developed LH-SMEDDS was composed of Capmul MCM C8 (oil), Cremophor EL (surfactant) and Transcutol HP (co-surfactant). Highest microemulsifying area was obtained at 3:1 ratio (surfactant:cosurfactant) and mean globule size was found to be 49.22 ±â€¯1.60 nm. More than 98% drug release was obtained with LH-SMEDDS in phosphate buffer pH 6.8. Confocal microscopy and flow cytometry studies revealed higher fluorescence indicating deeper penetration across Caco-2 cells with Coumarin-6 SMEDDS as compared to Coumarin-6 solution. Mean Fluorescence Intensity (MFI) with Coumarin-6 loaded SMEDDS was increased 25.57 times with respect to Coumarin-6 solution. The permeability across Caco-2 cells was enhanced 3 times with LH-SMEDDS as compared to LH-suspension. Furthermore, Area Under Curve with LH-SMEDDS was found to be 2.92 times higher than that of LH suspension indicating improved bioavailability after formulating SMEDDS. Lymphatic transport in oral absorption of LH-SMEDDS was proved via lymphatic uptake study. All the findings suggest the effectiveness of lipid-based formulation i.e. SMEDDS of LH to augment the oral bioavailability via intestinal lymphatic pathway.

C-reactive protein and response to lurasidone in patients with bipolar depression.

Prior studies suggest that the inflammatory biomarker c-reactive protein (CRP) holds promise for predicting antidepressant response in patients with major depressive disorder. The objective of this study was to evaluate whether CRP might similarly predict antidepressant responses to lurasidone in patients with bipolar I depression. Serum CRP concentration was measured prior to, and following, 6 weeks of treatment in 485 outpatients with bipolar I depression. Patients were randomized to receive monotherapy with lurasidone 20-60 mg/day (N = 161), lurasidone 80-120 mg/day (N = 162) or placebo (N = 162). CRP was assessed using the wide-range CRP assay (wr-CRP). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Mixed models and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP on clinical endpoints. CRP was evaluated as a log-transformed continuous variable and by clinically-relevant cut-points. Increasing pre-treatment wr-CRP level predicted a larger overall antidepressant response to lurasidone, as well as an increased response for a number of individual depressive symptoms. These moderating effects of pre-treatment wr-CRP remained significant after adjustment for potential confounds (e.g. baseline BMI and weight change). Treatment with lurasidone did not affect serum concentrations of CRP compared to placebo during the study. Elevated CRP level prior to treatment was associated with an enhanced clinical response to lurasidone in patients with bipolar I depression. If confirmed in future studies, CRP may represent a clinically useful diagnostic and predictive biomarker supporting a precision medicine approach to the treatment of bipolar depression.

The Effect of Chronic Treatment with Lurasidone on Rat Liver Cytochrome P450 Expression and Activity in the Chronic Mild Stress Model of Depression.

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg per os per day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects CYP (CYP2B, CYP2C11, and CYP3A), and its effects are different from those observed after other kinds of psychologic stress, such as repeated restraint stress or early-life maternal deprivation; 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11, and CYP3A isoforms; and 3) CMS modifies the action of lurasidone on CYP expression and function, leading to different effects of the neuroleptic in nonstressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g., steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11, or CYP3A, may proceed at a different rate in the two groups of animals (nonstressed and stressed) in the rat CMS model.