An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay

The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step-gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established.

Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers

Carbamazepine is a [CYP1A2 and CYP3A4 enzyme inducer] medicine which is used by epileptic patients for a long time. During the course of therapy, patients are generally caught by other diseases like urinary tract infections, upper respiratory tract infection, skin and soft tissue infection etc. To cure them, physicians commonly prescribe fluoroquinolones like Ciprofloxacin [CYP1A2 inhibitor] along with Carbamazepine [CBZ]. Interactions may result without recognition which may lead to unforeseen toxicity, untoward effects or even therapeutic failure. Therefore, studies were conducted to investigate the effect of Ciprofloxacin on the pharmacokinetics of Carbamazepine in healthy adult male volunteers. The main objective of this study was to generate new knowledge regarding CBZ and Ciprofloxacin interaction for physicians and research workers dealing with these medicines. Eight healthy adult male volunteers were selected to assess the effect of ciprofloxacin on the pharmacokinetics of Carbamazepine. After overnight fast the selected male volunteers were given CBZ orally. Blood samples were drawn at different time intervals after medication. Then the same volunteers were given CBZ along with ciprofloxacin. Blood samples were again drawn at the same time intervals as done previously. Plasma was separated from the blood samples. Concentration of CBZ in the plasma samples was determined by using HPLC technique. Results of the present study indicated that ciprofloxacin significantly increased the plasma concentration of CBZ when given concurrently to the healthy adult male volunteers. Ciprofloxacin increased C[max], AUC and t [1/2] while it decreased the CL and Vd of CBZ when administered concurrently to the adult volunteers. Change in pharmacokinetic parameters was due to slow metabolism or elimination of CBZ when given concurrently with ciprofloxacin to the adult volunteers. This is probably due to the inhibition of CYP3A4 isoenzyme by ciprofloxacin which is responsible for metabolism of CBZ. Ciprofloxacin increased the plasma concentration of CBZ so dose adjustment as well as drug monitoring of CBZ is required when both the drugs are given concurrently. The knowledge regarding interaction between ciprofloxacin and CBZ would be helpful for the pharmaceutical industries, physicians and a blessing for the patients

Farmacocinética poblacional de carbamacepina en pacientes epilépticos adultos / Population pharmacokinetics of carbamazepine in adults with epilepsy

The aim of the present study was to determinate the factors affecting carbamazepine (CBZ) clearance (CL) in adults with epilepsy using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 104 adults receiving CBZ. A total of 161 CBZ steady state serum concentration samples were analyzed. Population CL was calculated by using NONMEM with a one compartment model with first-order absorption and elimination. The following covariates were tested for their influence on clearance (CL): total body weight, age, dose/day, sex, surface area (SA) and comedication with primidone (PRIM), valproic acid or phenytoin (DFH). The final regression model for carbamazepine clearance found best to describe the data was: CL = (0.614 SA + 0.0016 dose/day)(1 + 0.278 DFH)(1 + 0.326 PRIM).

El objetivo de este trabajo es determinar los factores que influyen en el aclaramiento (CL) de carbamacepina (CBZ) en pacientes epilépticos adultos usando un modelo de efectos mixtos y datos de concentraciones séricas de CBZ generados del cuidado rutinario de los pacientes. El número de pacientes incluidos en el estudio fue de 104. Se analizaron un total de 161 concentraciones séricas de CBZ en el estado estacionario. El aclaramiento poblacional se determinó con el programa NONMEM aplicando un modelo monocompartimental con absorción y eliminación de primer orden. Se analizó la influencia de las siguientes covariables sobre el CL: peso corporal total, edad, dosis/día, sexo, superficie corporal (SC) y la comedicación con primidona (PRIM), ácido valproico o difenilhidantoína (DFH). El modelo final de regresión obtenido es el siguiente: CL = (0.614 SC + 0.0016 dosis/día)( 1+ 0.278 DFH)(1 + 0.326 PRIM).

Effect of honey on carbamazepine kinetics in rabbits.

The study was undertaken to determine the effect of honey on carbamazepine kinetics in rabbits. The study was done on three occasions in each animal. Study 1 was carried out after single dose administration of carbamazepine (80 mg/kg, po), along with saline (2.34 ml/kg, po). After a wash out period of one week, the second study was carried out by co-administration of carbamazepine with honey (2.34ml/kg, po). After this, the animals continued to receive honey (2.34ml/kg, po), once daily, for 7 days. On the eighth day of honey treatment, the carbamazepine kinetics was studied again. Pharmacokinetic analysis revealed that single as well as multiple dose honey treatment showed a significant decrease in area under the plasma time concentration curve (AUC) when compared with saline treated control. A significant increase in the clearance (CL/F) rate of carbamazepine was observed only after multiple dose honey treatment. Both single and multiple dose honey treatment did not show any significant effect on other pharmacokinetic parameters like t1/2, Cmax, Tmax and Vd when compared with saline treated group. Data thus obtained suggested that honey decreases the bioavailability of carbamazepine.

Comparison of absorption rate and bioavailability of two brands of carbamazepine.

OBJECTIVE: To assess the bioavailability of carbamazepine from two brands of carbamazepine--Tegretol 200 and Zen-200. METHODS: A two-way randomised cross-over bioavailability of carbamazepine was carried out in twelve healthy male volunteers. Coded plasma samples were analysed for levels of carbamazepine by high performance liquid chromatography (HPLC) method. Tegretol 200 and Zen-200 were tested for in-vitro dissolution profiles. RESULTS: The mean Cmax, Tmax and t1/2a for Tegretol 200 were: 2.17 +/- 0.42 mcg/mL, 11.67 +/- 6.37 h and 2.72 +/- 1.87 h; for Zen-200 were 3.10 +/- 0.05 mcg/mL, 3.50 +/- 2.11 h and 0.76 +/- 0.76 h respectively. These values were statistically significant. However AUC (0-96 h) value of 150.16 +/- 27.13 mcg/ml.h after Zen-200 was not statistically significant as compared to 128.68 +/- 20.22 mcg/ml.h after Tegretol 200. The in-vitro dissolution profiles of the two formulations were dissimilar. The fluctuations in CBZ levels after Tegretol 200 was significantly less as compared to Zen-200. The absorption profile as judged by parameter 'A' was 50.44 +/- 10.95 for Tegretol 200 and 42.49 +/- 18.89 for Zen-200. CONCLUSION: Based on parameter 'A' and other pharmacokinetic parameters, the marketed generic carbamazepine product, Zen-200 is not bioequivalent to Tegretol 200.

Preparation and pharmacokinetic evaluation of carbamazepine controlled release solid dispersion granules

Solvent evaporation technique was applied to prepare granules of carbamazepine coprecipitates using Eudragit RLPM, Eudragit RS 100, Cellulose acetate phthalate and Ethyl cellulose in 1: 1 and 1:2 drug: polymer w/w. In vitro release of carbamazepine from its coprecipitates with the previously mentioned polymers as well as the commercially available tablets [Tegretol CR200 tablets, Ciba] was carried out in gradient pH media [1.2, 2.5, 4.5, 7, 7.4] for 7 hours. The data were kinetically treated. Pharmacokinetic studies of the selected formula made with ethyl cellulose [1:1] and Tegretol CR 200 mg tablets [Ciba], as a reference standard, as well as carbamazepine powder were done using albino rabbits. Carbamazepine plasma level was determined using HPLC. The in vitro and in vivo data revealed that the suggested formula and the innovator's product exhibit% dissolution, tmax, Cpmax, AUC and /delta[1/2] as follows, 58.4%, 8 hr, 24.15 +/- 5.5/-microg/ml, 277.24hr microg/ml, 5.6hr and 64.22%, 8hr, 28.93 +/- 315.14 microg/ml, 313.6 hr, microg/ml, 5.2 hr respectively. It is worthy to note that the suggested formula showed a more prolonged duration of action

Variaciones farmacocinéticas de anticonvulsivantes en mujeres epilépticas mexicanas durante las diferentes etapas del postparto / Pharmakocinetic variation of anticonvulsants in Mexican epileptic women during different parts of puerperium

Durante el embarazo existen una serie de cambios fisiológicos que influyen en la cinética de los medicamentos administrativos durante esta etapa: Estos cambios fisiológicos no se restauran inmediatamente en el parto, de tal manera que su concentración en los fluidos biológicos es diferente cuando se administra inmediatamente después del parto que varias semanas posterior al mismo. El presente trabajo tiene como propósito identificar los cambios en las constantes farmacocinéticas de fenitoína y carbamacepina, en pacientes epilépticas cuando se mantiene una misma dosis durante diferentes etapas del postparto. En 20 mujeres mexicanas epilépticas se determinó la concentración en plasma y leche de fenitoína durante 60 días postparto y en 14 se determinó carbamacepina. A todas las pacientes se les realizó la farmacocinética de los anticonvulsivantes en cada periodo de estudio (5, 15, 30, 45 y 60 días posparto) y se determinó el índice de excreción en leche materna. Las concentraciones plasmáticas de fenitoína no presentaron variaciones, sin embargo la carbanacepina fue más alta en el periodo tardió, también se observaron diferencias en las áreas bajo la curva y vida media de eliminación y en los índices de excreción

Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy

We compared the efficacy and tolerance of the combination of nortriptyline-fluphenazine (NF) vs. carbamazepine (CNZ) in the symptomatic therapy of patients with severe, distal, symmetrical, predominantly sensitive diabetic polyneuropathy (DPN). We followed a double blind, crossover, randomized and double placebo design. Sixteen patients with severe DPN participated in the study. Patients received either NF (1 tablet three times a day (tid)), for 2 weeks. After this, patients received placebos of both drugs (wash-out period), until symptoms returned to baseline levels (100 percent), then they were crossed over to receive the other comparing drug schedule. A visual analoque scale was used to evaluate the percent changes in pain and paresthesia. HBA1, fasting serum glucose, and safety tests were performed at 2- and 4-week intervals, respectively. Both therapies produced significant improvement of both pain and paresthesis. No statistically significant differences were observed between both therapies for either pain or paresthesia. No significant biochemical changes were observed with any of the two therapies. Side effects were mild and more frequent in the NF period. In this study no superiority of either drug schedule was demonstrated; therefore, the decision to use any of them should be made according to the associated pathology and potential side effects of each drug

Carbamazepine kinetics in cardiac patients before and during amiodarone

Carbamazepina e amiodarona podem frequentemente ser usadas em conjunto, especialmente em países em que as cardiomiopatias säo comuns. Neste estudo doses de carbamazepina (400 mg) foram administradas a pacientes com doenças cardíacas antes e depois de um mês de terapia com amiodarona, 400 mg ao dia. O perfil cinético da carbamazepina, sua fraçäo livre e o nível sérico da amiodarona, foram avaliados nas duas ocasiöes. Näo foram observadas diferenças estatísticamente significantes na cinética da carbamazepina ou mesmo em sua fraçäo livre, antes e depois da introduçäo da amiodarona. A concentraçäo da amiodarona após um mês de terapia foi baixa. Conclui-se que a possível interaçäo no metabolismo hepático näo foi demonstrada devido as baixas concentraçöes de amiodarona, que provavelmente tenham sido suficientes para inibir o metabolismo da carbamazepina

Farmacocinesia de los medicamentos antiepilepticos / Antiepileptic drugs pharmacocinesia

Se hace una revisión de la literatura sobre la farmacología de los medicamentos anticomiciales. Se discute los aspectos más importantes de la farmacocinesia de las drogas a la luz de su importancia clínica. se examina algunos medicamentos por separado. Finalmete se presentan algunas recomendaciones sobre la suspensión de la medicación

Emprego da carbamazepina em doenças psiquiátricas / Use of carbamazepine in psychiatric diseases

O uso de carbamazepina no tratamento de doenças psiquiátricas é revisto. O mecanismo de açäo da carbamazepina pode ser relacionado a inibiçäo do Kindling (estimulaçäo elétrica subterapêutica repetida) no lobo temporal e no sistema límbico. Em muitos estudos já publicados, a carbamazepina foi útil no tratamento de distúrbios afetivos, especialmente em pacientes com distúrbios maníacos bipolares. Em estudos controlados, duplo-cegos, em pacientes com doenças afetivas primárias esquizoafetivas, a carbamazepina diminuiu significativamente os sintomas maníacos e mostrou efeito antidepressivo. Efeito sinergético foi observado quando a carbamazepina foi associada ao lítio. A carbamazepina também diminui sintomas em pacientes com agressäo, síndromes de descontrole, esquizofrenia e síndrome de síndrome de álcool, porém apenas poucos estudos foram controlados e comparativos; a carbamazepina pode ser útil em pacientes com aqueles distúrbios que näo respondam a terapias convencionais. Efeitos benéficos da carbamazepina em distúrbios psiquiátricos säo geralmente observados com doses de 400 a 1600 mg/dia e concentraçöes plasmáticas de 8-12 microng/ml. carbamazepina é útil em monoterapia ou combinada com outros agentes para distúrbios afetivos bipolares, especialmente em pacientes intolerantes ou que näo respondam ao lítio. Concentraçäo plasmática de carbamazepina, perfil hematológico e eletrólitos séricos devem ser monitorados cuidadosamente a fim de minimizar o risco de toxicidade