Nausea and vomiting in end-of-life care: managing this debilitating symptom in the community.

Nausea and vomiting (N&V) are common, debilitating and distressing symptoms for patients with advanced cancer, precipitating admission to hospital for intravenous antiemetic and re-hydration (Glare et al, 2011). The causes of N&V in end-of-life care (EOLC) are multifaceted, with appropriate therapy guided by thorough assessment (Walsh et al, 2017; Watson et al, 2019). Cyclizine and levomepromazine can, depending on aetiology, be cited as effective antiemetic agents for patients with advanced cancer (Ingleton and Larkin, 2015; Watson et al, 2019). Conversely, careful consideration of the use of dexamethasone for the management of N&V in EOLC should be taken, due to known side effects (Ferrel and Paice, 2019). This case study will use a systematic approach to critically appraise the management of N&V, experienced by a community patient receiving EOLC from the district nurses.

Movement disorders after hypoxic brain injury following cardiac arrest in adults.

BACKGROUND AND PURPOSE: Post-hypoxic movement disorders and chronic post-hypoxic myoclonus are rare complications after cardiac arrest in adults. Our study investigates the clinical spectrum, neuroimaging results, therapy and prognosis of these debilitating post-hypoxic sequelae. METHODS: This retrospective study included 72 patients from the neurological intensive care unit at a university hospital, who were diagnosed with hypoxic-ischaemic encephalopathy after cardiac arrest between January 2007 and September 2018. Clinical records were screened for occurrence of post-hypoxic movement disorders and chronic post-hypoxic myoclonus. Affected patients were further analysed for applied neuroprognostic tests, administered therapy and treatment response, and the outcome of these movement disorders and neurological function. RESULTS: Nineteen out of 72 screened patients exhibited post-hypoxic motor symptoms. Basal ganglia injury was the most likely neuroanatomical correlate of movement disorders as indicated by T1 hyperintensities and hypometabolism of this region in magnetic resonance imaging and positron emission tomography computed tomography. Levomepromazine and intrathecal baclofen showed first promising and mostly prompt responses to control these post-hypoxic movement disorders and even hyperkinetic storms. In contrast, chronic post-hypoxic myoclonus best responded to co-application of clonazepam, levetiracetam and primidone. Remission rates of post-hypoxic movement disorders and chronic post-hypoxic myoclonus were 58% and 50%, respectively. Affected patients seemed to present a rather good recovery of cognitive functions in contrast to the often more severe physical deficits. CONCLUSIONS: Post-hypoxic movement disorders associated with pronounced basal ganglia dysfunction might be efficiently controlled by levomepromazine or intrathecal baclofen. Their occurrence might be an indicator for a more unfavourable, but often not devastating, neurological outcome.

An autopsy case of heatstroke under the influence of psychotropic drugs.

We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the middle of August, with a high rectal temperature. Autopsy revealed congestion of the lungs without any specific findings. Quantitative toxicological analysis demonstrated concentrations of olanzapine, levomepromazine, 7-aminonitrazepam, and 7-aminoflunitrazepam in a femoral blood sample of 0.433 µg/mL, 0.177 µg/mL, 0.604 µg/mL, and 0.041 µg/mL, respectively. The concentration of olanzapine exceeded toxic levels; however, levomepromazine level was within the therapeutic range. Due to the blocking mechanism of both olanzapine and levomepromazine against muscarinic receptors, they might depress sweating and impair heat dissipation. Based on autopsy findings, results of toxicological examination, and investigation by the authorities, we concluded that the cause of death was heatstroke under the influence of olanzapine and levomepromazine.

The combination of levomepromazine (methotrimeprazine) and rotigotine enables the safe and effective management of refractory nausea and vomiting in a patient with idiopathic Parkinson's disease.

BACKGROUND:: This case report describes a patient with known idiopathic Parkinson's disease, being managed with transdermal rotigotine, whose refractory nausea and vomiting was successfully controlled with subcutaneous levomepromazine. No drug-induced extrapyramidal side effects emerged. CASE PRESENTATION:: A patient was found to have a locally advanced serous carcinoma, causing secondary bowel obstruction. Furthermore, due to compromised oral access, the patient's oral antiparkinsonian medications for motor control were converted to transdermal rotigotine. Unfortunately, the patient's nausea and vomiting was refractory to a number of recommended antiemetic options. CASE MANAGEMENT:: Low dose levomepromazine was administered on a, 'when required' basis, via subcutaneous injection. CASE OUTCOME:: After the first dose of levomepromazine, the patient's nausea and vomiting completely subsided and no extrapyramidal side effects were observed. This was confirmed by daily assessments, revealing no worsening of the motor symptoms associated with idiopathic Parkinson's disease. CONCLUSIONS:: The pharmacology of rotigotine and levomepromazine appear complementary and may allow for the simultaneous use of both drugs, with favourable outcomes. This case report highlights that rotigotine may afford protection against antipsychotic induced extrapyramidal side effects, while preserving antiemetic effects. Such combinations may have a role in the end-of-life management of idiopathic Parkinson's disease.

A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia.

OBJECTIVE: This study was a comparative investigation of the clinical efficacy and safety of intramuscular (IM) olanzapine, IM haloperidol, and IM levomepromazine in acute agitated patients with schizophrenia. METHODS: The subjects were 122 inpatients. Their clinical symptoms were assessed using Positive and Negative Syndrome Scale Excited Component (PANSS-EC), PANSS, and Agitation-Calmness Evaluation Scale, and their safety were assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale (BARS), and Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). RESULTS: The mean changes from baseline on the PANSS-EC, Agitation-Calmness Evaluation Scale, Abnormal Involuntary Movement Scale, BARS, and DIEPSS scores were significantly better in both IM olanzapine and IM levomepromazine than in IM haloperidol. Of these, the mean changes from baseline on the BARS and DIEPSS scores were significantly better in IM olanzapine than in IM levomepromazine. The mean change from baseline on the PANSS positive score was significantly better in both IM olanzapine and IM haloperidol than in IM levomepromazine. CONCLUSIONS: The results of this study suggest the possibility that the anti-agitation effects of IM olanzapine and IM levomepromazine are more rapid than those of IM haloperidol. No worsening of EPS was observed. Our results also suggest that compared with IM levomepromazine, IM olanzapine is safer and affords greater improvement in symptoms.

Comparison of Pharmacological Treatments for Agitated Delirium in the Last Days of Life.

CONTEXT: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. OBJECTIVES: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days. METHODS: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3. RESULTS: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics. CONCLUSION: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life.

CONTEXT: How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care. OBJECTIVES: To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety. METHODS: A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death. RESULTS: A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to -0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three. CONCLUSION: The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

Case of reversible Mobitz type II atrioventricular block after the use of injectable antipsychotics.

Although Mobitz type II atrioventricular block is typically an arrhythmia arising from a permanent organic disorder of the His-Purkinje system, reversible factors should also be considered. Here, we report the association between a rare reversible Mobitz type II atrioventricular block and antipsychotic medication in a 75-year-old patient with schizophrenia.

Antitumor Effect of Traditional Drugs for Neurological Disorders: Preliminary Studies in Neural Tumor Cell Lines.

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.

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. METHODS: The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6ß-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. RESULTS: The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. CONCLUSION: Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.

Chiral separation of four phenothiazines by nonaqueous capillary electrophoresis and quality by design-based method development for quantification of dextromepromazine as chiral impurity of levomepromazine.

The separation of the enantiomers of mepromazine, promethazine, thioridazine and alimemazine was studied by nonaqueous capillary electrophoresis in the presence of cyclodextrins using 1 M acetic acid and 50 mM ammonium acetate in methanol as background electrolyte. Heptakis(2,3-di-O-acetyl-6-O-sulfo)-ß-cyclodextrin, heptakis(2,3-di-O-methyl-6-O-sulfo)-ß-cyclodextrin (HDMS-ß-CD) and octakis(2,3-di-O-methyl-6-O-sulfo)-γ-cyclodextrin were the most effective chiral selectors for mepromazine, promethazine and alimemazine. Subsequently, a method for the determination of dextromepromazine as chiral impurity of levomepromazine was developed employing quality by design principles. Using HDMS-ß-CD as selector, a fractional factorial resolution V+ design was employed for evaluating the knowledge space, while a central composite face centered design provided further method optimization and the basis for the computation of the design space by Monte Carlo simulations. The final experimental conditions included a 30/40.2 cm fused-silica capillary with 75 µm inner diameter and a background electrolyte composed of 0.75 M acetic acid and 55 mM ammonium acetate in methanol containing 27.5 mg/mL HDMS-ß-CD. The applied voltage was 22 kV and the capillary temperature was 15°C. Following method robustness testing via a Plackett-Burman design, the method was validated for dextromepromazine in the range of 0.01 to 3.0 % relative to a concentration of 0.74 mg/mL levomepromazine and applied to the analysis of reference standards of the European Pharmacopoeia and commercial tablets. The assay also allowed the detection of levomepromazine sulfoxide although the quantitation of the compound was hampered by the poor peak shape of the late migrating diastereomer.

The effect of levomepromazine on the healthy and injured developing mouse brain - An in vitro and in vivo study.

Levomepromazine (LMP) is a phenothiazine neuroleptic drug with strong analgesic and sedative properties that is increasingly used off-label in pediatrics and is being discussed as an adjunct therapy in neonatal intensive care. Basic research points towards neuroprotective potential of phenothiazines, but LMP's effect on the developing brain is currently unknown. The aim of the present study was to assess LMP as a pharmacologic strategy in established neonatal in vitro and in vivo models of the healthy and injured developing mouse brain. In vitro, HT-22 cells kept exposure-naïve or injured by glutamate were pre-treated with vehicle or increasing doses of LMP and cell viability was determined. In vivo, LMP's effects were first assessed in 5-day-old healthy, uninjured CD-1 mouse pups receiving a single intraperitoneal injection of vehicle or different dosages of LMP. In a second step, mouse pups were subjected to excitotoxic brain injury and subsequently treated with vehicle or LMP. Endpoints included somatometric data as well as histological and immunohistochemical analyses. In vitro, cell viability in exposure-naïve cells was significantly reduced by high doses of LMP, but remained unaffected in glutamate-injured cells. In vivo, no specific toxic effects of LMP were observed neither in healthy mouse pups nor in experimental animals subjected to excitotoxic injury, but body weight gain was significantly lower following higher-dose LMP treatment. Also, LMP failed to produce a neuroprotective effect in the injured developing brain. Additional studies are required prior to a routine clinical use of LMP in neonatal intensive care units.

Fragmentation studies of selected drugs utilized in palliative care.

The results of research on selected drugs used in palliative care are presented, including fentanyl, tramadol, metoclopramide, hyoscine butylbromide, midazolam, haloperidol, levomepromazine and clonazepam. Interpretation of their ESI mass spectra obtained by the use of a triple quadrupole linear ion trap mass spectrometer is given. As a result, fragmentation pathways described in the literature are complemented and presented with more details. On their basis, transitions for quantitative analysis are selected and chromatographic conditions for the determination of the palliative care drugs are proposed as well. These results enable future studies on palliative care drugs in elderly patients including both their quantitation in body fluids and easier identification of their metabolites.

Simultaneous determination of dextromepromazine and related substances 2-methoxyphenothiazine and levomepromazine sulfoxide in levomepromazine on a cellulose tris(4-methylbenzoate) chiral column.

A high-performance liquid chromatography method for the determination of dextromepromazine, levomepromazine sulfoxide and 2-methoxyphenothiazine in levomepromazine samples was developed. The separation of the analytes was achieved within 10 min on a stationary phase containing cellulose tris(4-methylbenzoate) as chiral selector. The mobile phase consisted of 0.1% diethylamine in methanol with a flow rate of 1.0 mL/min. The method was validated according to the International Council for Harmonization guideline Q2(R1). The detection limits based on a signal-to-noise ratio of 3 were in the range of 0.002 to 0.005 µg/mL. The method proved to be precise and accurate in the concentration range of 0.025-1.0 % for levomepromazine sulfoxide and 2-methoxyphenothiazine and 0.025% to 3.0% for dextromepromazine relative to a concentration of 0.1 mg/mL of levomepromazine, with the exception of levomepromazine sulfoxide at the 0.1% level. The method was subsequently applied to the analysis of finished pharmaceutical products as well as of reference substances of the European Pharmacopoeia.

A quality by design-based approach to a capillary electrokinetic assay for the determination of dextromepromazine and levomepromazine sulfoxide as impurities of levomepromazine.

Using a quality by design approach, a capillary electrophoresis method for the simultaneous determination of dextromepromazine and the oxidation product levomepromazine sulfoxide in levomepromazine was developed. The analytical target profile was defined that the method should be able to quantify 0.1% of both impurities with a precision of ≤10%. Hydroxypropyl-γ-cyclodextrin was used as chiral selector. The critical process parameters cyclodextrin concentration, buffer pH and concentration as well as temperature and applied voltage were studied using a fractional factorial resolution V+ design for defining the knowledge space. A central composite face centered design was used as response surface methodology for deriving the design space by Monte Carlo simulations. The selected working point was a 100mM citric acid buffer, pH 2.85, containing 3.6mg/mL hydroxypropyl-γ-cyclodextrin, a temperature of 15°C and a voltage of 25kV. Robustness was estimated using a Plackett-Burman design. The method was subsequently validated in the relative concentration range of 0.1%-1.0% of the impurities for a solution containing 0.25mg/mL levomepromazine. The method was applied to the determination of the purity of the reference substance of the European Pharmacopoeia and of the drug in a commercial injection solution.

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy.

Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 µM (p < 0.01) and buclizine with a Kd of 433µM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.

Theoretical study on the metabolic mechanisms of levmepromazine by cytochrome P450.

Levomepromazine, an "older" typical neuroleptic, is widely applied in psychiatry for the treatment of schizophrenia. The biotransformation of Levomepromazine remains elusive up to now, but found to result in the formation of different derivatives that may contribute to the therapeutic and/or side-effects of the parent drug. The present work aims to resolve the metabolic details of Levomepromazine catalyzed by cytochrome P450, an important heme-containing enzyme superfamily, based on DFT calculation. Two main metabolic pathways have been addressed, S-oxidation and N-demethylation. The mechanistic conclusions have revealed a stepwise transfer of two electrons mechanism in S-oxidation reaction. N-demethylation is a two-step reaction, including the rate-determining N-methyl hydroxylation which proceeds via the single electron transfer (SET) mechanism and the subsequent C-N bond fission through a water-assisted enzymatic proton-transfer process. N-demethylation is more feasible than S-oxidation due to its lower activation energy and N-desmethyllevomepromazine therefore is the most plausible metabolite of Levomepromazine. Each metabolic pathway proceeds in a spin-selective manner (SSM) mechanism, predominately via the LS state of Cpd I. Our observations are in good accordance with the experimental results, which can provide some general implications for the metabolic mechanism of Levomepromazine-like drugs. Graphical abstract The metabolic mechanisms of levmepromazine by cytochrome P450.

Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neuroleptic levomepromazine: An in vitro study.

BACKGROUND: Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver. METHODS: The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6) and testosterone 6ß-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1-50 µM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection. RESULTS: Levomepromazine potently inhibited CYP2D6 (K(i) = 6 µM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 (K(i) = 47 µM) and CYP3A4 (K(i) = 34 µM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19. CONCLUSION: The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.

The cytochrome P450-catalyzed metabolism of levomepromazine: a phenothiazine neuroleptic with a wide spectrum of clinical application.

The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10µM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%). The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in catalyzing the above-mentioned reactions is negligible (0.1-8%). Moreover, at a higher, toxicological concentration of the neuroleptic (100µM), the relative contribution of CYP1A2 to levomepromazine metabolism visibly increases (from 20% to 28% for 5-sufoxidation, and from 8% to 32% for N-demethylation), while the role of CYP3A4 significantly decreases (from 72% to 59% for 5-sulfoxidation, and from 78% to 47% for N-demethylation). The obtained results indicate that the catalysis of levomepromazine 5-sulfoxidation and N-demethylation in humans shows a strict CYP3A4 preference, especially at a therapeutic drug concentration. Hence pharmacokinetic interactions involving levomepromazine and CYP3A4 substrates (e.g. tricyclic antidepressants, calcium channel antagonists, macrolide antibiotics, testosterone), inhibitors (e.g. ketoconazole, erythromycin, SSRIs) or inducers (e.g. rifampicin, carbamazepine) are likely to occur.

The influence of amitriptyline and carbamazepine on levomepromazine metabolism in human liver: an in vitro study.

BACKGROUND: Joint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the present study was to investigate possible effects of the tricyclic antidepressant drug amitriptyline and the anticonvulsant drug carbamazepine on the metabolism of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. METHODS: The experiment was performed in vitro using human liver microsomes. The rates of levomepromazine 5-sulfoxidation and N-demethylation (levomepromazine concentrations: 5, 10, 25 and 50µM) were assessed in the absence and presence of amitriptyline or carbamazepine added in vitro (drug concentrations: 1, 2.5, 5, 10, 25µM). RESULTS: A kinetic analysis of levomepromazine metabolism carried out in the absence or presence of carbamazepine showed that the anticonvulsant drug potently inhibited levomepromazine 5-sulfoxidation (Ki=7.6µM, non-competitive inhibition), and moderately decreased the rate of levomepromazine N-demethylation (Ki=15.4µM, mixed inhibition) at therapeutic drug concentrations. On the other hand, amitriptyline weakly diminished the rate of levomepromazine 5-sulfoxidation (Ki=63µM, mixed inhibition) and N-demethylation (Ki=47.7µM, mixed inhibition). CONCLUSION: Regarding the central and peripheral effects of levomepromazine and some of its metabolites, the observed metabolic interaction between this neuroleptic and carbamazepine may be of pharmacological and clinical importance.