RESUMO
In this paper, paper microfluidic channel fabricated by directly screen-printing of polydimethylsiloxane (PDMS) is proposed for paper spray mass spectrometry analysis of therapeutic drugs in the blood samples. Compared with traditional paper spray, PDMS-printed paper spray (PP-PS) allows fluid to flow to the tip of paper with less sample loss which significantly improved the signal intensity of target compounds in blood samples. As paper can reduce the matrix effect, PP-PS also has a greater advantage than electro-spray Ionization (ESI) when directly analyzing complex biological sample in terms of the detection efficiency. Linearity and limits of detection (LOD) were evaluated for five psychotropic drugs: olanzapine, quetiapine, 9-hydroxyrisperidone, clozapine, risperidone. As a result, PP-PS improved the signal intensity of the psychotropic drugs at a concentration of 250 ng/ml in blood samples by a factor of 2-5 times and lowered the relative standard deviation (RSD) by a factor of 2-5.6 times compared with traditional paper spray. And PP-PS also improved signal intensity by a factor of 9-33 times compared with ESI. Quantitative experiments of PP-PS mass spectrometry indicated that the linear range was 5-500 ng/ml and the LOD were improved by a factor of 5-71 times for all these drugs compared with traditional paper spray. In addition, PP-PS was applied to the home-made miniaturized mass spectrometer and the precursor ions of all five psychotropic drugs (250 ng/ml) in the mass spectrometry results were obtained as well. These could prove that PP-PS has the potential to analyze complex biological samples in application on the miniaturized mass spectrometer which can be used outside the laboratory.
Assuntos
Dimetilpolisiloxanos , Espectrometria de Massas , Papel , Humanos , Dimetilpolisiloxanos/química , Espectrometria de Massas/métodos , Limite de Detecção , Clozapina/sangue , Risperidona/sangue , Fumarato de Quetiapina/sangue , Palmitato de Paliperidona/sangue , Olanzapina/sangue , Psicotrópicos/sangue , ImpressãoRESUMO
We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.
Assuntos
Antipsicóticos , Infecções Respiratórias , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Aripiprazol/sangue , Aripiprazol/uso terapêutico , Clozapina/sangue , Clozapina/uso terapêutico , Humanos , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/uso terapêutico , Infecções Respiratórias/sangue , Infecções Respiratórias/tratamento farmacológico , Risperidona/sangue , Risperidona/uso terapêuticoRESUMO
PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.
Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Heterozigoto , Farmacogenética , Adulto , Toxicologia Forense , Humanos , Masculino , Paroxetina/sangue , Paroxetina/farmacocinética , Fenótipo , Risperidona/sangue , Risperidona/farmacocinética , Serotoninérgicos/sangue , Serotoninérgicos/farmacocinética , Transtornos Relacionados ao Uso de Substâncias/complicações , Cloridrato de Venlafaxina/sangue , Cloridrato de Venlafaxina/farmacocinéticaRESUMO
A systematic approach to develop a UPLC-MS/MS method was applied for quantifying of risperidone (RISP), its active metabolite, 9-hydroxy risperidone (9-OH-RISP) and internal standard (propranolol) in rat plasma. Liquid-liquid extraction was performed using methyl tert-butyl ether for quantification of drug and its active metabolite by MS detection in the positive ion mode. Acquity UPLC system with BEH C18 (2.1 mm × 100 mm, particle size 1.7 µm) column was used along with acetonitrile (0.1% formic acid)-2 mM (milli mole) ammonium acetate in isocratic condition was used as the mobile phase. Detection was performed by multiple reactions monitoring with precursor-to-product ion transitions with m/z 411.2 â 191.0 for RISP, m/z 427.2 â 207.0 for 9-OH-RISP and m/z 260.1 â 116.0 for IS. The method was validated as per the FDA guidance on bioanalytical method validation. Linearity (r2 = 0.999) was observed in the drug concentration ranging between 0.1 and 50 ng mL-1, while all other parameters were found to be within the acceptable ranges. Method robustness was optimized by Box-Behnken design to monitor the influential variables to achieve maximal recovery of the analytes in the rat plasma. Pharmacokinetic evaluation of the analytes from long-acting microparticles in rat plasma showed two peaks indicating an initial burst effect within 24 h of administration followed by controlled drug release pattern upto 45 days, while marketed formulation (Risperdal Consta®) showed no plasma concentration during the lag-time of 21 days followed by maximal drug absorption between 28 and 40 days.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Risperidona/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Preparações de Ação Retardada , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Risperidona/química , Risperidona/farmacocinéticaRESUMO
Separation of antipsychotic drugs from whole blood and urine is of great importance for clinic and forensic laboratories. In this work, chlorprothixene, haloperidol and risperidone representing the first and second generations of antipsychotic drugs were studied. Among them, chlorprothixene and risperidone were investigated for the first time by electromembrane extraction (EME). After the screening, 2-nitrophenyl octyl ether (NPOE) was used as the supported liquid membrane (SLM). The EME performance for spiked water (pH 2), whole blood and urine was tested and optimized individually. Using NPOE and 60 V, efficient EME was achieved from urine and whole blood with trifluoroacetic acid as the acceptor solution. The equilibrium time required for EME was dependent on the sample matrices. The steady-state of EME was reached in 30 min and 20 min for whole blood and urine, respectively. At steady-state, the EME recoveries of the targets from different sample matrices were satisfactory, and were in the range of 74%-100%. The proposed EME approach combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was evaluated using whole blood and urine. The obtained linearity was 1-200 ng mL-1, and the coefficient of determination (R2) was ≥ 0.9853 for haloperidol and ≥ 0.9936 for chlorprothixene and risperidone. The limit of detection (LOD) and accuracy for all the targets ranged from 0.2-0.6 ng mL-1 and 102%-110%, respectively, and the repeatability at low (1 ng mL-1), medium (10 ng mL-1) and high (200 ng mL-1) concentration was ≤ 12% (RSD). Finally, the validated approach was successfully used to determine chlorprothixene, risperidone and haloperidol in whole blood and urine from rats, which were treated with chlorprothixene, risperidone and haloperidol at low therapeutic dose, respectively.
Assuntos
Clorprotixeno/sangue , Clorprotixeno/urina , Eletricidade , Haloperidol/sangue , Haloperidol/urina , Membranas Artificiais , Risperidona/sangue , Risperidona/urina , Ácidos/química , Animais , Antipsicóticos/sangue , Antipsicóticos/química , Antipsicóticos/urina , Líquidos Corporais , Clorprotixeno/química , Cromatografia Líquida , Haloperidol/química , Humanos , Masculino , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Risperidona/química , Solventes/química , Espectrometria de Massas em Tandem , Fatores de Tempo , Água/químicaRESUMO
Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.
Assuntos
Antipsicóticos/sangue , Detecção do Abuso de Substâncias/métodos , Adulto , Amissulprida/sangue , Aripiprazol/sangue , Benzodiazepinas/sangue , Cromatografia Líquida , Clozapina/sangue , Dibenzotiazepinas/sangue , Feminino , Toxicologia Forense , Humanos , Masculino , Olanzapina/sangue , Palmitato de Paliperidona/sangue , Piperazinas/sangue , Fumarato de Quetiapina/sangue , Estudos Retrospectivos , Risperidona/sangue , Esquizofrenia/tratamento farmacológico , Suicídio , Sulpirida/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangueRESUMO
This article describes a method for the simultaneous quantitation of risperidone and its major metabolite, 9-hydroxyrisperidone, in beagle dog plasma by field-amplified sample injection in capillary zone electrophoresis. The separation was carried out at 25°C in a 48 cm × 75 µm fused-silica capillary with an applied voltage of 20 kV using 60 mM NaH2 PO4 buffer (pH 3.6). The detection wavelength was 280 nm. Clean-up and preconcentration of plasma samples were conducted by 96-well formatted liquid-liquid extraction. In this study, this stacking technique provided a sensitivity enhancement of approximately 158 to 188 fold compared with the same sample without stacking. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision, and extraction recovery. Calibration curves exhibited good linearity (r2 > 0.995) over a wide concentration range of 2.5 to 200 ng/mL for both risperidone and 9-hydroxyrisperidone. The intra- and interday precisions at the three quality control levels were less than 11.40%. The intra- and interday accuracies ranged from 87.90 to 107.17% for risperidone and from 88.43 to 105.92% for 9-hydroxyrisperidone. All validation data were within the required limits. In conclusion, the method developed was successfully applied to pharmacokinetic studies of risperidone and 9-hydroxyrisperidone in beagle dogs.
Assuntos
Análise de Injeção de Fluxo , Palmitato de Paliperidona/sangue , Risperidona/sangue , Animais , Cães , Eletroforese Capilar , Feminino , Masculino , Estrutura Molecular , Palmitato de Paliperidona/metabolismo , Palmitato de Paliperidona/farmacocinética , Risperidona/metabolismo , Risperidona/farmacocinéticaRESUMO
BACKGROUND: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified. OBJECTIVE: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system. METHODS: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens. RESULTS: A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies. CONCLUSION: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.
Assuntos
Antipsicóticos/farmacocinética , Citocromo P-450 CYP2D6/genética , Risperidona/farmacocinética , Antipsicóticos/sangue , Citocromo P-450 CYP2D6/metabolismo , Humanos , Polimorfismo Genético , Risperidona/sangueRESUMO
Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.
Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/administração & dosagem , Risperidona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Antipsicóticos/sangue , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/diagnóstico , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Risperidona/sangueRESUMO
BACKGROUND: Antidepressants and antipsychotics are widely prescribed drugs for the treatment of mental diseases. Therapeutic drug monitoring (TDM) is recommended for patients taking these drugs to ensure pharmaceutical efficacy, medication compliance and prevent toxicity. OBJECTIVE: An ultra-high performance liquid chromatography/tandem-mass spectrometry (UPLC-MS/ MS) method was developed for simultaneous determination of two Antidepressants-Fluoxetine (FLU) and Escitalopram (ESC), and two antipsychotics-risperidone (RIS) and aripiprazole (ARI), in human plasma. METHODS: The sample was processed by simple protein precipitation and the targeted analytes were separated on a C18 column by gradient elution with a mobile phase containing 0.1% formic acid (v/v) and acetonitrile. All the analytes were qualitative and quantitative measured by electrospray ionization source with Multiple Reaction Monitoring (MRM) in positive ion mode. A total of 56 plasma samples were obtained from out- or in-patients who were taking the cited four drugs for further analysis. RESULTS: The calibration curves for FLU, ESC, RIS and ARI were linear in the range of 45-1800, 4-320, 2-200 and 50-1800 ng/mL, respectively. The entire analytical time for the analytes was 7.0 min for each run and the extraction efficiency was more than 90%. The sample was stable within various storage conditions. The trough concentrations in patients were measured with the validated method. CONCLUSION: The developed method was successfully used for simultaneous determination of FLU, ESC, RIS and ARI in the plasma of the patients, which provides effective technical support for routine TDM of these four drugs and is of great clinic value for individual therapy.
Assuntos
Antidepressivos/sangue , Antipsicóticos/sangue , Aripiprazol/sangue , Citalopram/sangue , Fluoxetina/sangue , Risperidona/sangue , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Humanos , Espectrometria de Massas em TandemRESUMO
BACKGROUND AND OBJECTIVES: The genetic polymorphism of cytochrome P450 (CYP) 2D6 is characterized by an excessive impact on positive and adverse drug reactions to antipsychotics, such as risperidone. Consequently, the pharmacokinetics of the drug and metabolite can be substantially altered and exhibit a high variability between the different phenotypes. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for risperidone and 9-hydroxyrisperidone (9-OH-RIS) taking CYP3A4 into account. Additionally, risperidone dose adjustments, which would compensate for genetically caused differences in the plasma concentrations of the active moiety (sum of risperidone and 9-OH-RIS) were calculated. METHODS: Based on available knowledge about risperidone, 9-OH-RIS, and relevant physiological changes according to different CYP2D6 phenotypes, several PBPK models were built. In addition, an initial model was further evaluated based on the plasma concentrations of risperidone and 9-OH-RIS from a single-dose study including 71 genotyped healthy volunteers treated with 1 mg of oral risperidone. RESULTS: PBPK models were able to accurately describe risperidone exposure after single-dose administration, especially in the concentration range ≥ 1 µg/L, illustrated by a minimal bias and a good precision. About 90.3% of all weighted residuals versus observed plasma concentrations ≥ 1 µg/L were in the ± 30% range. The risperidone/9-OH-RIS ratio increased progressively according to reduced CYP2D6 activity, resulting in a mean ratio of 4.96 for poor metabolizers. Simulations demonstrate that dose adjustment of the drug by - 25% for poor metabolizers and by - 10% for intermediate metabolizers results in a similar exposure to that of extensive metabolizers. Conversely, the risperidone/9-OH-RIS ratio can be used to determine the phenotype of individuals. CONCLUSION: PBPK modelling can provide a valuable tool to predict the pharmacokinetics of risperidone and 9-OH-RIS in healthy volunteers, according to the different CYP2D6 phenotypes taking CYP3A4 into account. These models are able to ultimately support decision-making regarding dose-optimization strategies, especially for subjects showing lower CYP2D6 activity.
Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Palmitato de Paliperidona/farmacocinética , Risperidona/farmacocinética , Administração Oral , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Antipsicóticos/farmacocinética , Tomada de Decisão Clínica , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP3A/efeitos dos fármacos , Feminino , Genótipo , Humanos , Masculino , Modelos Teóricos , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/efeitos adversos , Palmitato de Paliperidona/sangue , Fenótipo , Polimorfismo Genético , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Risperidona/sangueRESUMO
Magnesium oxide (MgO) is a widely used laxative. Because many antipsychotic drugs are lipophilic-basic-compounds, their solubility decreases with increasing pH and changes markedly as the pH of the solution approaches their pKa. It is highly important to clarify the effect of co-administration of MgO on the serum drug concentration for effective, safe, and appropriate medication therapy. However, the relationship between MgO administration and the serum concentration of antipsychotic drugs in patients with schizophrenia has not been reported. Therefore, in the present study, we investigated the effect of MgO administration on the concentration of antipsychotic drugs in the blood of patients with schizophrenia. The serum concentrations of biperiden, zotepine, and risperidone were assayed using an LC/MS system. The correlation between the daily dose of MgO and the relative-drug-concentration (rCp) in each patient was examined. As the MgO dose was increased, the risperidone concentration decreased. The correlation coefficient decreased for risperidone, zotepine, and biperiden, in the same order. To clarify the difference in the suppression potency of MgO on the three drugs, the relationship between the physical properties and the correlation coefficients of each drug was carefully examined. A strong correlation was observed between the pKa and the correlation coefficient. Patients with schizophrenia are often prescribed antipsychotic drugs, which have anticholinergic action and tend to suppress gastric acid secretion. We concluded that basic drug absorption might be suppressed due to an increase in the stomach pH following MgO administration. Therefore, MgO co-administration is better to avoid while taking antipsychotic drugs and anticholinergic drugs.
Assuntos
Antipsicóticos/farmacocinética , Laxantes/farmacologia , Óxido de Magnésio/farmacologia , Esquizofrenia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/sangue , Biperideno/sangue , Biperideno/farmacocinética , Dibenzotiepinas/sangue , Dibenzotiepinas/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Pessoa de Meia-Idade , Risperidona/sangue , Risperidona/farmacocinética , Esquizofrenia/tratamento farmacológicoRESUMO
Non-adherence to antipsychotic medication is a primary factor in disease relapse in schizophrenic patients. We sought to evaluate if plasma concentrations of the antipsychotic risperidone can be used as a predictor of treatment adherence and to identify the optimal plasma concentration threshold to reliably distinguish between adherent and non-adherent patients. A population pharmacokinetic model was used to simulate plasma risperidone steady-state trough concentrations in 1000 virtual patients, where 60% of the patients were 100% adherent to their medication, while 40% of the patients were non-adherent to their medication. The probability of adherence was assessed by receiver operating characteristic (ROC) analysis on Ctrough. The area under the ROC curve (AUCROC) was used to identify the optimal Ctrough threshold. Single vs multiple Ctrough at steady state was also evaluated. After a single risperidone Ctrough measurement, the AUCROC (95% CI) was estimated to be 0.71 (0.69-0.72) and the optimal Ctrough threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple Ctrough measurements, the AUCROC (95% CI) increased up to 0.85 (0.84-0.87) for three Ctrough measurements. The optimal probability threshold to reliably discriminate between adherent and non-adherent patients was estimated to be 0.51. Using this model which is reflective of typical adherence to antipsychotic medication, we found that three consecutive steady-state Ctrough measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.
Assuntos
Antipsicóticos/farmacocinética , Monitoramento de Medicamentos/métodos , Adesão à Medicação , Risperidona/farmacocinética , Esquizofrenia/tratamento farmacológico , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Reações Falso-Negativas , Reações Falso-Positivas , Humanos , Modelos Biológicos , Valor Preditivo dos Testes , Curva ROC , Risperidona/sangue , Risperidona/uso terapêutico , Esquizofrenia/sangueRESUMO
High-dose antipsychotic(s) can induce dopamine supersensitivity psychosis in schizophrenia patients. The precise relationship between a drug's blood concentration and the occurrence of dopamine supersensitivity psychosis has not been established. We divided 36 patients with schizophrenia who had undergone treatment mainly with risperidone into two groups: one with normal metabolizing activity of CYP2D6 (n = 15), and the other with lower activity of its variant, CYP2D6*10 (n = 21). The patients' blood concentrations of risperidone and 9-OH-risperidone were measured, and we compared the occurrence of dopamine supersensitivity psychosis episodes between the groups. There was no significant difference in any concentration of risperidone, 9-OH-risperidone, or active moiety between the groups although the with-CYP2D6*10 group had greater variabilities of these parameters compared to the without-CYP2D6*10 group. There was a lower rate of dopamine supersensitivity psychosis episodes in the without-CYP2D6*10 group (4/15, 26.7%) compared to the with-CYP2D6*10 group (11/21, 52.4%), but the difference was not significant. Although our findings were negative, largely because of the small sample size, these results suggest that (1) patients with an impaired functional allele of CYP2D6 may have higher concentrations of risperidone and its active metabolite and that (2) these patients may experience more frequent dopamine supersensitivity psychosis episodes.
Assuntos
Citocromo P-450 CYP2D6/metabolismo , Dopamina/fisiologia , Psicoses Induzidas por Substâncias/tratamento farmacológico , Risperidona/metabolismo , Esquizofrenia/tratamento farmacológico , Alelos , Antipsicóticos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Genótipo , Humanos , Palmitato de Paliperidona/sangue , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Risperidona/sangue , Risperidona/uso terapêutico , Esquizofrenia/genéticaRESUMO
Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK-Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood-brain barrier parameters including the expression and efflux transport kinetics of P-glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations in brainECF, drug-D2 receptor binding kinetics (association and dissociation rates) were incorporated in MoBi to predict RO. From an extensive literature search, 32 plasma PK data sets (16 from rat and 16 from human studies) and 23 striatum RO data sets (13 from rat and 10 from human studies) were prepared and compared with the model predictions. The rat PBPK-RO model adequately predicted the plasma concentrations of the parent drugs and metabolites and the RO levels. The human PBPK-RO model also captured the plasma PK and RO levels despite the large interindividual and interstudy variability, although it tended to underestimate the plasma concentrations and RO measured at late time points after risperidone dosing. The developed human PBPK-RO model was successfully applied to predict the plasma PK and RO changes observed after risperidone dose reduction in a clinical trial in schizophrenic patients.
Assuntos
Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Modelos Biológicos , Receptores de Dopamina D2/metabolismo , Animais , Antipsicóticos/sangue , Antipsicóticos/farmacologia , Clozapina/análogos & derivados , Clozapina/sangue , Clozapina/farmacocinética , Clozapina/farmacologia , Antagonistas dos Receptores de Dopamina D2/sangue , Antagonistas dos Receptores de Dopamina D2/farmacologia , Feminino , Humanos , Cinética , Masculino , Palmitato de Paliperidona/sangue , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/farmacologia , Ratos , Risperidona/sangue , Risperidona/farmacocinética , Risperidona/farmacologia , Pesquisa Translacional BiomédicaRESUMO
Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.
Assuntos
Antidepressivos/sangue , Antipsicóticos/sangue , Fumar/sangue , Fumar/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amitriptilina/sangue , Clozapina/análogos & derivados , Clozapina/sangue , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Succinato de Desvenlafaxina/sangue , Doxepina/análogos & derivados , Doxepina/sangue , Monitoramento de Medicamentos , Feminino , Glucuronosiltransferase , Humanos , Masculino , Pessoa de Meia-Idade , Mirtazapina/sangue , Nortriptilina/sangue , Palmitato de Paliperidona/sangue , Fumarato de Quetiapina/sangue , Estudos Retrospectivos , Risperidona/sangue , Cloridrato de Venlafaxina/sangueRESUMO
AIM: The role of sex on the association of plasma prolactin levels with risperidone (R) and 9-hydroxyrisperidone (9-OHR) concentrations is investigated. METHODS: Plasma R and prolactin concentrations, CYP2D6 and exon 21 and 26 ABCB1 gene variants were studied in 110 patients. RESULTS: In females, a 1 ng/ml increase in R levels was associated with a significant 1.02% increase in prolactin levels. In males, a 1 ng/ml increase in 9-OHR levels was associated with a significant 1.18% increase in prolactin levels. ABCB1 haplotype 12 had significant but opposite effects in males and females. In the combined sample, 9-OHR, but not R levels had significant effects on prolactin levels. CONCLUSION: Genes had sex-specific effects on risperidone-associated prolactin elevations.
Assuntos
Citocromo P-450 CYP2D6/genética , Prolactina/sangue , Risperidona/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/sangue , Prolactina/genética , Risperidona/uso terapêutico , Caracteres SexuaisRESUMO
OBJECTIVE: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes. METHODS: ABLs from 694 patients who were randomized to olanzapine or risperidone were compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency room visit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessed with treatment failure within 100â¯days of drug concentration measurement were analyzed. RESULTS: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLs within/above RR). The difference between groups was significant (odds ratioâ¯=â¯1.810; 95% CIâ¯=â¯1.025, 3.197; pâ¯=â¯0.0408). CONCLUSIONS: Analysis of CATIE data showed that ABLs within the context of RRs may identify patients with higher risk of relapse.
Assuntos
Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Antipsicóticos/efeitos adversos , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Olanzapina/efeitos adversos , Olanzapina/sangue , Olanzapina/uso terapêutico , Recidiva , Risperidona/efeitos adversos , Risperidona/sangue , Risperidona/uso terapêutico , Falha de Tratamento , Adulto JovemAssuntos
Monitoramento de Medicamentos , Inflamação/sangue , Risperidona/sangue , Risperidona/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicaçõesRESUMO
BACKGROUND: Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug monitoring of antipsychotics. To facilitate implementation in clinical practice, the aim of this study was to perform a clinical validation study of a DBS method for quantification of risperidone, aripiprazole, pipamperone, and their major metabolites 9-OH risperidone and dehydro-aripiprazole in a real-life, clinical setting. METHODS: Paired DBS and venous plasma samples were analyzed (n = 35 for risperidone, n = 21 for aripiprazole, n = 21 for pipamperone). Estimated plasma concentrations were calculated from DBS concentrations based on hematocrit and/or Deming regression formulas. Deming regression and Bland-Altman analyses were used to determine the agreement between the calculated and measured plasma concentrations. For Bland-Altman analysis, the following acceptance limit was used: for a minimum of 67% of the samples, the difference of the 2 measurements should be within 20% of their mean. RESULTS: The median venous plasma levels were 0.9 mcg/L for risperidone, 14.8 mcg/L for 9-OH risperidone, 135.4 mcg/L for aripiprazole, 54.9 mcg/L for dehydro-aripiprazole, and 56.4 mcg/L for pipamperone. All antipsychotics required different correction formulas of DBS concentrations for best agreement. Subsequently, no constant or proportional bias was observed using Deming regression analysis. With Bland-Altman analyses, for risperidone, 45% of the samples were within the 20% limits; for 9-OH risperidone, 36%; for aripiprazole, 45%; for dehydro-aripiprazole, 35%; and for pipamperone, 43%. CONCLUSIONS: The DBS method to quantify risperidone, aripiprazole, pipamperone, and their major metabolites did not meet the acceptance criteria in the Bland-Altman analyses. Therefore, this DBS method was not clinically valid. This study shows the importance of a clinical validation study with use of Bland-Altman plots before clinical implementation.