Detection of Carbamazepine and Its Metabolites in Blood Samples by LC-MS/MS / 法医学杂志

OBJECTIVES@#To establish a method for the detection of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS).@*METHODS@#The blood samples were treated with 1-butyl-3-methylimidazolium hexafluorophosphate as an extraction solvent. The samples were extracted by ultrasound-assisted extraction and separated by ZORBAX Eclipse Plus C18, 95Å column. The mobile phase A aqueous solution containing 0.1% formic acid and 10 mmol/L ammonium acetate, and mobile phase B mixed organic solvent containing acetonitrile/methanol (Vacetonitrile∶Vmethanol=2∶3) were used for gradient elution at the flow rate of 1.00 mL/min. An electrospray ion source in positive mode was used for detection in the multiple reaction monitoring.@*RESULTS@#The linearities of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples were good within the corresponding range, with correlation coefficients (r) greater than 0.995 6. The limits of detection were 3.00, 0.40 and 1.30 ng/mL, respectively. The limit of quantitation were 8.00, 1.00 and 5.00 ng/mL, respectively. The extraction recoveries ranged from 76.00% to 106.44%. The relative standard deviations of the intra-day and inter-day precisions were less than 16%. Carbamazepine and its main metabolite 10,11-dihydro-10,11-epoxycarbamazepine were detected in blood samples of death cases with a mass concentration of 2.71 μg/mL and 252.14 ng/mL, respectively.@*CONCLUSIONS@#This method has high sensitivity and good selectivity, which is suitable for the detection of carbamazepine and its metabolites in blood samples, and can be used for carbamazepine-related forensic identifications.

Thermoanalytical studies of carbamazepine: hydration/dehydration, thermal decomposition, and solid phase transitions

Carbamazepine (CBZ), a widely used anticonvulsant drug, can crystallize and exhibits four polymorphic forms and one dihydrate. Anhydrous CBZ can spontaneously absorb water and convert to the hydrate form whose different crystallinity leads to lower biological activity. The present study was concerned to the possibility of recovering the hydrated form by heating. The thermal behavior of spontaneously hydrated carbamazepine was investigated by TG/DTG-DTA and DSC in dynamic atmospheres of air and nitrogen, which revealed that the spontaneous hydration of this pharmaceutical resulted in a Form III hydrate with 1.5 water molecules. After dehydration, this anhydrous Form III converted to Form I, which melted and decomposed in a single event, releasing isocyanic acid, as shown by evolved gas analysis using TG-FTIR. Differential scanning calorimetry analyses revealed that Form III melted and crystallized as Form I, and that subsequent cooling cycles only generated Form I by crystallization. Solid state decomposition kinetic studies showed that there was no change in the substance after the elimination of water by heating to 120 °C. Activation energies of 98 ± 2 and 93 ± 2 kJ mol-1 were found for the hydrated and dried samples, respectively, and similar profiles of activation energy as a function of conversion factor were observed for these samples.

A carbamazepina (CBZ) é um anticonvulsivante frequentemente utilizado no Brasil e em vários países. Ela apresenta quatro formas polimórficas e um diidrato. Todas as formas são ativas farmacologicamente, porém a Forma III é a preferível do ponto de vista farmacêutico, em função de suas propriedades físico-químicas. Entretanto, essa forma é altamente higroscópica, podendo converter-se ao diidrato, menos ativo biologicamente. Nesse trabalho propõe-se avaliar o comportamento térmico da forma hidratada, visando à recuperação da forma ativa, por aquecimento. Para tanto, foi feito um estudo do comportamento térmico por TG/DTG-DTA e DSC em atmosfera dinâmica de ar e nitrogênio, que evidenciou hidratação espontânea da Forma III, gerando um hidrato contendo 1,5 moléculas de água. Essa forma sofre desidratação, seguida de fusão e conversão para a Forma I. Segue-se a decomposição em uma única etapa, na qual ocorre liberação do ácido isociânico, conforme análise de gases evolvidos, por termogravimetria acoplada ao infravermelho (TG-FTIR). Estudos por calorimetria exploratória diferencial mostraram que a Forma III se funde e se cristaliza imediatamente na Forma I, durante o aquecimento. A Forma I também se funde e ciclos de aquecimento/resfriamento posteriores evidenciaram que a substância se cristaliza apenas na Forma I por resfriamento. Estudos cinéticos da decomposição, em estado sólido, mostraram que não há alteração na substância pela eliminação da água por aquecimento, sendo determinados valores de energia de ativação da ordem de 98 ± 2 e 93 ± 2 kJ mol-1, respectivamente, para a amostra hidratada e submetida à secagem, assim como perfis semelhantes nas curvas de energia de ativação em função do fator de conversão.

Bioequivalencia de una formulación cubana de carbamazepina con el producto líder / Bioequivalent of a Cuban formula of Carbamazepine with the leader product

Se demostró la intercambiabilidad terapéutica mediante un estudio de bioequivalencia en 25 voluntarios sanos de una formulación cubana de carbamazepina de 200 mg con respecto al producto innovador (Tegretol®), en condiciones de administración a dosis única; el diseño experimental fue cruzado a doble ciegas y aleatorizado; el periodo de lavado fue de 15 días. Las extracciones para la obtención del plasma, se realizaron a las 0; 0,5; 1; 1,5; 2; 3; 4; 6; 8; 10; 12; 16; 20; 24; 48; 72; 96 y 120 h. Para el análisis se empleó un método analítico por cromatografía líquida de alta eficiencia, isocrático en fase reversa con detección ultravioleta. Se estimaron mediante técnicas no compartimentales los parámetros farmacocinéticos (AUC0-t, AUCt-¥, Cmax, Tmax y T1/2) representativos de la biodisponibilidad en magnitud y velocidad. Sobre la base de los resultados estadísticos, ambas formulaciones resultaron bioequivalentes.

It was possible to demonstrate the therapeutic interchange level by means of a bioequivalence study in 25 healthy volunteers of a Cuban formula of Carbamazepine(200 mg) according to the innovative product (Tegretol®) for a administration of unique dose; the experimental design was of crossed, double-blind and random type; washing period was of 15 days. Extractions for plasma obtaining were performed at 0, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours. In analysis we used an analytical method by high performance liquid chromatography, isocratic type in reverse phase with UV detection. By means of non-compartment techniques pharmacokinetic parameters (AUC0-t, AUC t-¥, Cmax, Tmax, and T½) were estimated, which are representative of bioavailability in magnitude and speed. On the base of statistical results, both formulae were bioequivalent.

Relación entre niveles de carbamazepina en saliva y plasma: Estudio piloto / Saliva and plasma levels of carbamazepine have a poor correlation: a pilot study

Abstract: Carbamazepine is one of the most commonly used anticonvulsants for the treatment of epilepsy and its plasma concentrations must be monitored periodically to obtain a useful and safe clinical effect. There is not a good relationship between the dose of the carbamazepine and their effects in humans, but the effects of this drug have been well correlated with its plasma levels. Aim: To measure the correlation between plasma and saliva levels of carbamazepine in children with epilepsy. Material and Methods: Saliva and plasma levels of carbamazepine were measured by using instrumental planar chromatography in 11 epileptic children aged 8 to 15 years treated with the drug for at least six months. Results: The mean saliva/plasma ratio was 0.18±0.05 and the mean of carbamazepine concentration in saliva, expressed as a percentage of concentrations in plasma, was 17.97±5.40. There was a poor linear correlation (r =0.37) between the concentrations of carbamazepine in both fluids. Conclusions: In this group of epileptic children the correlation between saliva and plasma carbamazepine levels was weak.

rapid high performance liquid chromatographic determination of lansoprazole in human serum

A simple and rapid reverse phase high-performance liquid chromatographic [RP-HPLC] method with UV detection has been described for the determination of lansoprazole in human serum. Carbamazepine was used as internal standard. The drug and the internal standard in serum were extracted twice with diethyl ether, followed by evaporation, reconstitution in the mobile phase and injection into the chromatographic system. The method utilized a Nova-Pak CI8 4-micro m column [150x3.9 mm i.d.] together with an isocratic mobile phase consisted of 0.02M sodium dihydrogenphosphate- acetonitrile- methanol [58: 23: 19%, v/v/v]. The mobile phase was adjusted to pH 7.3 with 5M NaOH and pumped at a flow rate of 1.8 mI/min. The UV detector was set at 285 Rm. Running time per single analysis was less than four minutes. The response of the assay was linear with a correlation coefficient, r = 0.9993. The within and between-day coefficients of variation for three different concentrations [50-1500 ng/ml] ranged from 1.14 to 8.26% and from 1.66 to 8.02%, respectively. The average recovery of the concentration range stated was better than 96.5%. Stability testing revealed that lansoprazole was stable in serum at -20°C for two weeks. The method was successfully applied in a bioassay study of two products each in the form of enteric-coated granules in capsules containing 30 mg lansoprazole, administered orally to eighteen healthy male volunteers

Lítio, Carbamazepina e Acido Valpróico: eficácia na fase de manutençäo / Lithium, carbamazepine and valproate: efficacy in the prophylaxis of bipolar disorder

Neste artigo, foi feita uma revis

Determinacao de carbamazepina-10,11 epoxido em plasma por cromatografia gas-liquido / GLC determination of carbamazepine and 10,11 epoxide carbamazepine in plasma

Foi proposto um metodo para determinacao de carbamazepina (CBZ) e carbamazepina-10,11 epoxido (CBZ-E) por cromatografia gas-liquido (CG), sem derivacao, com uso de lidocaina como padrao interno, detector de ionizacao de chama e coluna 5 por cento Apiezon L - 0,5 por cento KOH. O metodo mostrou-se com precisao, exatidao e sensibilidade adequadas para a monitorizacao de niveis plasmaticos terapeuticos de CBZ e CBZ-E em pacientes submetidos a monoterapia ou politerapia anticonvulsivante

Quantificacao da carbamazepina e carbamazepina-10,11-epoxoxido em plasma por cromatografia liquida de alta eficiencia com finalidade de controle terapeutico / Quantification of carbamazepine and carbamazepine-10,11-epoxide by high performance liquid chromatography for therapeutic control

Foi desenvolvido um metodo empregando a cromatografia liquida de alta eficiencia para a quantificacao de carbamazepina e carbamazepina-10,11-epoxido em plasma com finalidade de controle terapeutico. Os farmacos foram extraidos com diclorometano, em meio alcalino,e cromatografados em coluna de fase reversa (C-18), usando acetonitrila: agua (1:1) como fase movel e deteccao em 220 nm. O metodo mostrou-se preciso com coeficientes de variacao para analise intra-ensaio de 2,8 e 3,8%, para a carbamazepina e seu epoxido, respectivamente. A precisao inter-ensaios foi de 4,4 e 4,7%. O metodo mostrou-se adequado para a analise da carbamazepina em plasma de pacientes sob mono ou politerapia