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1.
Forensic Sci Int ; 307: 110108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877542

RESUMO

Quetiapine is an atypical antipsychotic drug, frequently found in post-mortem samples. The quantitative determination of active metabolites may help in the interpretation of the potential toxic effects of the parent drug and its role in death. A fully validated LC-MS/MS method was developed for the identification and quantification of quetiapine and two main metabolites (N-desalkylquetiapine and 7-hydroxyquetiapine) in blood, biological fluids and tissues. Then, the distribution of analytes in different matrices was evaluated. LODs of 0.9, 0.3 and 0.3ng/mL were calculated for quetiapine, N-desalkylquetiapine and 7-hydroxyquetiapine respectively; while a LOQ at the concentration of 10.0ng/mL was defined for the three analytes. 13 post-mortem positive real cases have been included in the experiment. The results revealed that quetiapine and N-desalkylquetiapine might undergo a significant post-mortem redistribution, while 7-hydroxyquetiapine is less affected by this factor. N-desalkylquetiapine could be found in blood in relatively high concentrations in comparison to those of quetiapine; therefore, it should be always advisable to measure both the analytes. The analysis of tissues could provide additional data on potential intoxication with quetiapine.


Assuntos
Antipsicóticos/farmacocinética , Mudanças Depois da Morte , Fumarato de Quetiapina/farmacocinética , Tecido Adiposo/química , Adulto , Idoso , Bile/química , Química Encefálica , Cromatografia Líquida , Dibenzotiazepinas/farmacocinética , Feminino , Toxicologia Forense , Humanos , Rim/química , Limite de Detecção , Fígado/química , Pulmão/química , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Baço/química , Espectrometria de Massas em Tandem , Distribuição Tecidual , Adulto Jovem
2.
Drug Des Devel Ther ; 13: 255-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30643391

RESUMO

Objective: The objectives of this study were to evaluate the bioequivalence of Quesero extended release (Quesero XR) tablets and Seroquel extended release (Seroquel XR) tablets under fasting and fed conditions and to determine the effect of food on the pharmacokinetic (PK) properties of Quesero XR or Seroquel XR in Chinese healthy volunteers. Methods: A single-site, randomized, open-label, two-period crossover design with a 10-day washout period was conducted in 20 subjects under the fed and fasting studies. A single oral dose of 200 mg Quesero XR or Seroquel XR was given to the subjects after an overnight fast of 10 hours. Blood samples were taken at scheduled time spots from 0 hour pre dose to 36 hours post dose. Plasma concentrations of quetiapine were measured by a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The PK parameters were calculated by non-compartment analysis using Phoenix WinNonlin software. Results: On both conditions, no significant differences were found among the main PK parameters of the two preparations by analysis of variance (P>0.05); the Wilcoxon test of maximum peak plasma concentration (Tmax) showed no significant differences (P>0.05); the 90% confidence limit (CL) of lnCmax, lnAUC0→36, and lnAUC0→∞ fell within the acceptable range of 80%-125%. As compared with the fasting state, the Tmax was advanced and the mean maximum plasma concentration (Cmax), AUC0→36, and AUC0→∞ were also increased in the fed state; the geometric mean ratio and 90% CI of the main PK parameters fell outside the range of the CIs; analysis of variance showed significant differences in the other PK parameters except for apparent total clearance after oral administration (clearance rate; P<0.05). Conclusion: The two formulations of Quesero XR and Seroquel XR are bioequivalent under both fasting and fed conditions, and food may affect the PK profiles by increasing the rate and extent of absorption of Quesero XR or Seroquel XR in Chinese healthy volunteers.


Assuntos
Jejum/sangue , Interações Alimento-Droga , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacocinética , Administração Oral , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fumarato de Quetiapina/sangue , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
3.
Clin Toxicol (Phila) ; 57(4): 271-281, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30306811

RESUMO

OBJECTIVE: Extended release (ER) tablets/capsules in massive ingestion overdoses are prone to form pharmacobezoars potentially increasing the risk of late-appearing toxic effects and prolonged symptoms. Oral activated charcoal is often sufficient to prevent drug absorption, but in a recent massive ingestion of highly toxic substances, prior orogastric lavage might be considered. The disintegration characteristics of ER preparations in overdose situations is valuable to understand if the time line and course of the intoxication might be prolonged, but information on these characteristics are unavailable. Slow disintegration and/or pharmacobezoar formation, and the large size makes ER preparation impossible to evacuate using a 30F orogastric lavage tube. This study evaluates the disintegration and pharmacobezoar formation of a simulated massive ER tablet ingestion in an in vitro model, using a selection of extended release tablets, with different disintegrating characteristics when present in therapeutic numbers. Furthermore, the sizes of the formed pharmacobezoars were compared with the dimensions of a 30F orogastric lavage tube. METHOD: A standardized model mimicking the physical effects on pharmaceutical preparations in simulated gastric fluid (SGF) was developed and tested on three mono-depot ER tablets (quetiapine/Seroquel®XR 50 mg, paracetamol/Pinex®Retard 500 mg, verapamil/Isoptin®Retard 240 mg), one poly-depot ER tablet (carbamazepine/Tegretol®Retard 200 mg), and one immediate-release tablet (paracetamol/Panodil® 500mg). Thirty tablets were placed in polyamide mesh bags, either together in one bag or in separate bags, immersed in 1 L SGF, and incubated at 37 °C for 48 h. Released drugs were quantified at 0.5-48 h. RESULTS: Visual inspection showed that Seroquel®XR, Pinex®Retard, and Isoptin®Retard tablets formed firm pharmacobezoars stable for more than 4 h and intact fractions remained for up to 24 h. Drug releases were reduced by 53%, 40%, and 31%, respectively, for up to 8 h compared to separated tablets. Light microscopy showed that contact with SGF transformed the coating of Seroquel®XR and Pinex®Retard to a diffusion-controlled swelled gel-layer, and the Isoptin®Retard tablets into a rigid and slow-releasing matrix. Tegretol®Retard disintegrated into microspheres within 30 min, and Panodil® disintegrated within minutes. DISCUSSION: The developed pharmacobezoars of mono-depot ER tablets demonstrated prolonged drug release. Neither the formed pharmacobezoars, nor the single tablets of the tested mono-depot ER preparations, would pass through the lumen of a standard orogastric lavage tube, rendering this modality ineffective for tablet removal in gastrointestinal decontamination.


Assuntos
Bezoares/etiologia , Preparações de Ação Retardada/farmacocinética , Acetaminofen/efeitos adversos , Acetaminofen/química , Acetaminofen/farmacocinética , Carbamazepina/efeitos adversos , Carbamazepina/química , Carbamazepina/farmacocinética , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Overdose de Drogas , Suco Gástrico , Humanos , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/química , Fumarato de Quetiapina/farmacocinética , Comprimidos/efeitos adversos , Comprimidos/química , Comprimidos/farmacocinética , Verapamil/efeitos adversos , Verapamil/química , Verapamil/farmacocinética
4.
Tijdschr Psychiatr ; 60(8): 548-551, 2018.
Artigo em Holandês | MEDLINE | ID: mdl-30132584

RESUMO

In this article we describe the developments of two patients who were hospitalized after a quetiapine overdose, subsequently developing delirium. Delirium occurred several hours after ingestion and lasted several days. Laboratory blood testing revealed a slower decline in quetiapine plasma concentration than expected when compared to the standardized half-life averages of therapeutic doses of quetiapine. The clinical state during the first hours after ingestion does not sufficiently predict further clinical outcome. The changes in pharmacokinetics due to the intoxication, so-called toxicokinetics, are the underlying cause.


Assuntos
Antipsicóticos/efeitos adversos , Delírio/induzido quimicamente , Fumarato de Quetiapina/efeitos adversos , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Overdose de Drogas , Feminino , Humanos , Masculino , Fumarato de Quetiapina/farmacocinética , Fumarato de Quetiapina/uso terapêutico
5.
J Clin Psychopharmacol ; 38(4): 362-364, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29912789

RESUMO

BACKGROUND: Risk assessment of the use of quetiapine during breastfeeding is challenging owing to a paucity of data. METHODS: A pharmacokinetic study was conducted in lactating women who were taking quetiapine. The primary endpoint was to determine quetiapine concentration profiles in milk and estimated infant exposure levels. Multiple milk and a single blood quetiapine concentrations were determined using a highly sensitive liquid chromatography with tandem mass spectroscopy method. RESULTS: Nine subjects receiving fast-release quetiapine (mean dose, 41 mg/d) were analyzed at steady state. The mean milk/plasma drug concentration ratio at 2-hour postdose was 0.47 (SD, 0.50; range, 0.13-1.67). The mean milk concentration of each patient was 5.7 ng/mL (SD, 4.5; range, 1.4-13.9 ng/mL). The mean infant quetiapine dose via milk per body weight relative to weight-adjusted maternal dose was 0.16 % (SD, 0.08; range, 0.04%-0.35%). CONCLUSIONS: Infant exposure levels to quetiapine via milk are predicted to be very small.


Assuntos
Antipsicóticos/farmacocinética , Leite Humano/química , Fumarato de Quetiapina/farmacocinética , Antipsicóticos/análise , Antipsicóticos/sangue , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Fumarato de Quetiapina/análise , Fumarato de Quetiapina/sangue , Espectrometria de Massas em Tandem
6.
Drug Deliv ; 25(1): 916-927, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29649903

RESUMO

The current study aimed to rationally develop and characterize pH-sensitive controlled release hydrogels by graft polymerization of gelatin (Gel) and hydroxypropyl methyl cellulose (HPMC) in the presence of glutaraldehyde (GA) using quetiapine fumarate for the treatment of schizophrenia. The prepared hydrogels discs were subjected to various physicochemical studies including: swelling, diffusion, porosity, sol-gel analysis, Fourier transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Three different pH values (1.2, 6.8 and 7.4) were used to determine shape, transition, and controlled release behavior of prepared hydrogels. Various kinetic models including zero order, first order, Higuchi model and Power Law equation were applied on drug release data. The optimized hydrogels were subjected to in vivo studies using albino rabbits. Swelling and release results were found to be insignificant (p < .05) evidencing that there was no significant difference in swelling and drug release rate of hydrogels in different pH mediums. Swelling, porosity, gel-fraction, and drug released (%) were found to be dependent on concentrations of Gel, HPMC, and GA. Kinetic models revealed that QTP-F release followed non-Fickian diffusion. In-vivo studies contributed significantly higher plasma QTP-F concentration (Cmax), time for maximum plasma concentration (Tmax), area under the curve (AUC0-inf) and half-life (t1/2) as 18.32 ± 0.50 µg/ml, 8.00 ± 0.01 hrs, 6021.2 ± 5.09 µg.hrs/ml and 10.06 ± 0.43 hrs, respectively, for test-hydrogels when compared to reference market brand (Qusel® 200 mg, Hilton Pharma, Karachi, Pakistan) QTP-F tablets. It might be concluded that QTP-F loaded pH-sensitive hydrogels were developed successfully with reduced dosing frequency for schizophrenia.


Assuntos
Antipsicóticos/farmacocinética , Portadores de Fármacos , Gelatina/química , Derivados da Hipromelose/química , Fumarato de Quetiapina/farmacocinética , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/química , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Difusão , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrogéis , Concentração de Íons de Hidrogênio , Masculino , Microscopia Eletrônica de Varredura , Modelos Biológicos , Modelos Químicos , Porosidade , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/química , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier , Tecnologia Farmacêutica/métodos
7.
Artigo em Inglês | MEDLINE | ID: mdl-29702137

RESUMO

Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V0 (n = 153) and co-medication with quetiapine, VQUE (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype. The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co-medicated group. Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine.


Assuntos
Fármacos do Sistema Nervoso Central/farmacocinética , Fumarato de Quetiapina/farmacocinética , Cloridrato de Venlafaxina/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos do Sistema Nervoso Central/sangue , Fármacos do Sistema Nervoso Central/uso terapêutico , Preparações de Ação Retardada , Succinato de Desvenlafaxina/sangue , Interações de Medicamentos , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/uso terapêutico , Estudos Retrospectivos , Cloridrato de Venlafaxina/sangue , Cloridrato de Venlafaxina/uso terapêutico , Adulto Jovem
8.
Eur J Clin Pharmacol ; 74(5): 593-599, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29392351

RESUMO

BACKGROUND: Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. AIMS: The aim of this study was to develop "reference ranges" for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. METHODS: Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. RESULTS: Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7-41.6 ng/mL 0-4 h post dose and 10.6-37.1 ng/mL 20-24 h post dose. These ranges increased to 221-624 ng/mL 0-4 h post dose following administration of a 30-mg dose, and 159-557 ng/mL 20-24 h post dose. The 80% reference range 0-4 h post dose was 22.5-67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179-768 ng/mL following a 150-mg dose once daily of oral quetiapine. CONCLUSIONS: Comparing individual patients' APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.


Assuntos
Antipsicóticos/sangue , Aripiprazol/sangue , Benzodiazepinas/sangue , Modelos Biológicos , Fumarato de Quetiapina/sangue , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/farmacocinética , Aripiprazol/farmacocinética , Benzodiazepinas/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Fumarato de Quetiapina/farmacocinética , Valores de Referência , Adulto Jovem
10.
Am J Hosp Palliat Care ; 35(8): 1076-1080, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29343085

RESUMO

In the absence of suitable oral or intravenous access for medication administration and when the intramuscular medications are undesirable, alternative routes for drug delivery may be considered. Antipsychotics administered via an inhaled, intranasal, rectal, or topical route have been described in the literature. Topically administered antipsychotics have been previously reported to produce negligible systemic absorption despite being used in clinical practice for nausea and behavioral symptoms associated with dementia. Additionally, the American Academy of Hospice and Palliative Medicine recommends against the use of topical medications that lack supporting literature. Three studies have assessed the systemic absorption of different antipsychotics after administration of only a single, topically applied dose. To evaluate whether the repeated administration of a topically applied antipsychotic may result in detectable serum levels in an accumulating fashion, a pharmacokinetic study was conducted. Five healthy, adult participants consented to receive extemporaneously prepared topical quetiapine in Lipoderm every 4 hours for a total of 5 doses. Blood samples were drawn at baseline and hours 2, 4, 8, 12, 16, and 24, and serum quetiapine concentrations were measured using high-performance liquid chromatography. Quetiapine was undetectable in every sample from 3 participants. Two participants had minimally detectable serum quetiapine levels no sooner than hour 12 of the study period. Extemporaneously prepared quetiapine in Lipoderm resulted in nonexistent or minimal serum level following repeated topical administration. The use of topically applied quetiapine should still be questioned.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Demência/tratamento farmacológico , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacocinética , Administração Cutânea , Adulto , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/uso terapêutico
11.
Int J Neuropsychopharmacol ; 21(2): 108-113, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016993

RESUMO

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.


Assuntos
Inibidores da Captação Adrenérgica , Antidepressivos/farmacocinética , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Dibenzotiazepinas/sangue , Hipotálamo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Fumarato de Quetiapina/farmacocinética , Reboxetina , Adulto , Antidepressivos/administração & dosagem , Transtorno Bipolar/diagnóstico por imagem , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Locus Cerúleo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fumarato de Quetiapina/administração & dosagem , Adulto Jovem
12.
Int J Clin Pharmacol Ther ; 56(1): 38-42, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29198307

RESUMO

AIM: This study was conducted in order to compare the bioavailability of two film-coated tablets containing 25 mg of quetiapine. METHODS: 24 subjects were enrolled in and completed a single-center, randomized, single-dose, open-label, two-way crossover study with a 1-week washout period. Plasma samples were collected up to 24 hours following drug administration; thus, quetiapine was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with turbo-ion-spray mode. The pharmacokinetic parameters used for bioequivalence assessment were AUC0-t, AUC0-∞, and Cmax. The 90% confidence intervals were obtained by analysis of variance for AUC0-t, AUC0-∞, and Cmax. RESULTS: The results were all within the range of 80.00 - 125.00%. CONCLUSION: Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.
.


Assuntos
Antipsicóticos/farmacocinética , Fumarato de Quetiapina/farmacocinética , Adolescente , Adulto , Cromatografia Líquida , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
13.
Curr Drug Deliv ; 15(6): 818-828, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28545354

RESUMO

BACKGROUND: Lymphatic route is one of the prominent routes for improving the poor bioavailability of the drugs which undergo extensive hepatic first pass metabolism. Nanocarriers (solid lipid nanoparticles) offer a new drug delivery system that could hold great promise for attaining the bioavailability enhancement along with controlled and site specific drug delivery. OBJECTIVE: The aim of the present research work was to prepare and optimized the Quetiapine fumarate (an antipsychotic drug) loaded solid lipid nanoparticles for lymphatic targeting through intraduodenal administration. METHOD: Thirteen quetiapine fumarate loaded solid lipid nanoparticle formulations were developed using different lipids by Microemulsion technique and optimized by box behnken design. RESULTS: Optimized formulation (Q9) had a mean particle size of 230.38 nm with 75.92% of entrapment efficiency. The percentage drug release after 24 h was found to be 95.81%. A significant difference (P<0.05) was found in the in vitro release data of optimized formulation as compared to marketed formulation. In vitro release data of optimized formulation (Q9) was subjected to zero order, first order and Higuchi model to evaluate the release kinetics. Higuchi model was found to be the best fitted model with highest value of correlation coefficient (R2= 0.999). In vivo studies for optimized solid lipid nanoparticles formulation and drug suspension were performed on male Wistar rats after intraduodenal administration and several pharmacokinetic parameters were determined. AUC (0-∞) of optimized formulation was significantly (P<0.01) more than that of drug suspension. Bioavailability of quetiapine in solid lipid nanoparticles was 2.76 fold increased after intraduodenal administration as compared with that of drug suspension. CONCLUSION: On the basis of results of in vitro study, Q9 formulation was selected as optimized formulation. It exhibited better bioavailability as compared to drug suspension. It can be concluded that solid lipid nanoparticles are potential carrier for improving quetiapine bioavailability through lymphatic delivery.


Assuntos
Antipsicóticos/farmacocinética , Sistemas de Liberação de Medicamentos , Lipídeos/química , Linfonodos/efeitos dos fármacos , Nanopartículas/química , Fumarato de Quetiapina/farmacocinética , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/química , Disponibilidade Biológica , Infusões Intralesionais , Linfonodos/metabolismo , Masculino , Tamanho da Partícula , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/química , Ratos , Ratos Wistar
14.
Bipolar Disord ; 19(6): 477-486, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28833962

RESUMO

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.


Assuntos
Transtorno Bipolar , Catecol O-Metiltransferase/genética , Ácido Fólico , Fumarato de Quetiapina , Triazinas , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Escalas de Graduação Psiquiátrica Breve , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacocinética , Humanos , Lamotrigina , Masculino , Testes Farmacogenômicos , Psicotrópicos/administração & dosagem , Psicotrópicos/farmacocinética , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacocinética , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/farmacocinética
15.
Br J Clin Pharmacol ; 83(11): 2398-2405, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28585378

RESUMO

AIM: 4ß-Hydroxycholesterol (4ßOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4ßOHC levels and steady-state concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients. METHODS: Serum samples from 151 patients treated with quetiapine as immediate release (IR; n = 98) or slow release (XR; n = 53) tablets were included for analysis of 4ßOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 h post-dosing for IR and XR tablets, respectively. Correlations between 4ßOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (≥60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis. RESULTS: Correlations between 4ßOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P < 0.0001). Estimated Spearman r values were -0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4ßOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P < 0.001), including gender (P = 0.023) and age (P = 0.003) as significant covariates. CONCLUSIONS: The present study shows that 4ßOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4ßOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.


Assuntos
Antipsicóticos/farmacocinética , Biomarcadores Farmacológicos/sangue , Citocromo P-450 CYP3A/metabolismo , Hidroxicolesteróis/sangue , Transtornos Mentais/tratamento farmacológico , Fumarato de Quetiapina/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Feminino , Humanos , Masculino , Transtornos Mentais/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Fumarato de Quetiapina/uso terapêutico , Fatores Sexuais , Comprimidos , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-28578191

RESUMO

A selective, sensitive and simple high performance liquid chromatography tandem mass spectrometric (HPLC-MS/MS) method for determining quetiapine in human plasma was developed and validated. One-step protein precipitation with acetonitrile was used to pretreat plasma samples. Carbamazepine was used as internal standard. An automated liquid handling workstation with 96-well protein precipitate plate was used to facilitate the process. The chromatographic separation was achieved on a Waters Xbridge C18 column (3.5µm, 2.1mm×50mm). Gradient elution was set with a mobile phase of acetonitrile/water (containing 10mM ammonium acetate and 0.1% formic acid).The flow rate was 0.4mL/min and total analytical run time was 3min. The analysis was conducted using a triple quadrupole tandem mass spectrometer with an electrospray ionization source operating in positive ion mode. The multiple reaction monitoring of transition were m/z 384.2→253.1 for quetiapine and m/z 237.0→194.0 for carbamazepine, respectively. The linear concentration range for the standard curve of quetiapine was 0.5-400ng/mL for a 5µL injection of the pretreated sample (original plasma sample, 50µL). The intra-day and inter-day accuracy and precision were all less than 15%. The method was successfully used in a bioequivalence study comparing two quetiapine extended-release tablets in Chinese volunteers.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Preparações de Ação Retardada , Humanos , Modelos Lineares , Masculino , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Equivalência Terapêutica
17.
Drug Dev Ind Pharm ; 43(8): 1330-1342, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28402145

RESUMO

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro-in vivo correlations.


Assuntos
Conteúdo Gastrointestinal/química , Derivados da Hipromelose/química , Polímeros/química , Fumarato de Quetiapina/metabolismo , Fumarato de Quetiapina/farmacocinética , Comprimidos/farmacocinética , Tampões (Química) , Química Farmacêutica , Preparações de Ação Retardada , Conteúdo Gastrointestinal/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Concentração Osmolar , Fumarato de Quetiapina/química , Solubilidade , Comprimidos/química , Viscosidade
18.
J Pharmacol Sci ; 133(3): 139-145, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28279595

RESUMO

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.


Assuntos
Antipsicóticos/administração & dosagem , Hiperglicemia/induzido quimicamente , Fumarato de Quetiapina/administração & dosagem , Animais , Antipsicóticos/sangue , Antipsicóticos/farmacocinética , Glicemia/análise , Relação Dose-Resposta a Droga , Glucose/metabolismo , Hiperglicemia/sangue , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/farmacocinética
19.
Neuro Endocrinol Lett ; 38(7): 475-478, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29369597

RESUMO

OBJECTIVES: Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS: In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. RESULTS: No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. CONCLUSION: We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.


Assuntos
Antimaníacos/farmacocinética , Antipsicóticos/farmacocinética , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/farmacocinética , Fumarato de Quetiapina/farmacocinética , Adulto , Antimaníacos/sangue , Antimaníacos/uso terapêutico , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Transtorno Bipolar/sangue , Carbamazepina/sangue , Carbamazepina/uso terapêutico , Interações de Medicamentos , Feminino , Humanos , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/uso terapêutico
20.
Chem Pharm Bull (Tokyo) ; 64(11): 1546-1554, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27803466

RESUMO

Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pKa, solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses. The plasma QTP and NQTP concentrations in rats were determined by a fully-validated liquid-chromatography tandem mass spectrometry (LC-MS/MS). Over the investigated dosing range, both QTP and NQTP showed linear pharmacokinetics. Following oral administration of the same dose, the area under the concentration-time curve (AUC0-∞) and maximum serum concentration (Cmax) were larger after NQTP administration compared to QTP administration. In addition, NQTP had a greater absolute oral bioavailability compared to QTP (15.6% vs. 0.63%, respectively). The brain-to-plasma concentration ratio was greater after NQTP administration compared to the QTP and NQTP ratios after QTP administration. NQTP administration results in increased systemic exposure and brain distribution compared to QTP administration. Future studies are needed to evaluate the pharmacologic and toxicologic effects of increased NQTP exposures.


Assuntos
Encéfalo/metabolismo , Dibenzotiazepinas/metabolismo , Dibenzotiazepinas/farmacocinética , Microssomos Hepáticos/metabolismo , Fumarato de Quetiapina/metabolismo , Fumarato de Quetiapina/farmacocinética , Administração Oral , Animais , Química Física , Dibenzotiazepinas/administração & dosagem , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Masculino , Microssomos Hepáticos/química , Fumarato de Quetiapina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual
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