Interaction of carbamazepine and promethazine in rabbits

The interaction of carbamazepine and promethazine in rabbits has been investigated. The influence of this interaction on the processes of biotransformation in the liver was revealed. The drugs were administered as single oral doses (100 mg of each drug) as well as simultaneously with an interval of 15 min. The sequence of administration of the drugs was varied. The influence of promethazine on the pharmacokinetics of carbamazepine is expressed by: (a) strong suppression of carbamazepine's level in plasma and appearance of multiple peaks of carbamazepine; (b) suppression of biotransformation of carbamazepine into carbamazepine-10,11-epoxide at the initial stages and its increase in the intermediate stages. These data are explained by the active capture of carbamazepine by liver at its primary transferal through the liver and sufficient presystem elimination of carbamazepine in the presence of promethazine. The character of kinetic curves of promethazine varies substantially under the influence of carbamazepine. However, this change is not as strong as in case of carbamazepine. The concentration of promethazine in plasma varies slightly and multiple peaks are not observed. The rate of terminal elimination of promethazine varies and abrupt prolonged segments of elimination appear at the initial and terminal stages of the process in return. These data perhaps indicate the induction of biotransformation of promethazine in the presence of carbamazepine-an inductor of microsomal liver enzymes. The changes of kinetics of promethazine and carbamazepine by simultaneous administration as compared with their administration separately, as well as a comparative consideration of pharmacokinetics of promethazine and carbamazepine by simultaneous administration show the existence of competition in the elimination between these drugs and the periodic saturation of liver for their biotransformation.     

Interaction of carbamazepine and chlorpromazine in rabbits.

The interaction of carbamazepine and chlorpromazine in rabbits has been studied. The drugs were administrated as single oral doses (200 mg of each drug). The sequence of administration of the drugs was varied. It has been established that by simultaneous administration these drugs decrease absorption of each other in plasma. This may be explained by competition of the drugs to transfer from the gastrointestinal tract into plasma, as well as by the formation of complexes, more or less stable and more or less bound to gastrointestinal tissues. Carbamazepine intensifies the biotransformation of chlorpromazine, which may be caused by the ability of carbamazepine to induce microsomal liver enzymes. Chlorpromazine suppresses the biotransformation of carbamazepine, however. This may be caused by intensive capture of chlorpromazine by liver tissues and by its intensive biotransformation, which in turn is conditioned by its surface-active nature and by the increase of its metabolism with carbamazepine. Therefore the biotransformation of chlorpromazine is increased and metabolism of carbamazepine is reduced. The sequence of administration of the drugs affects their pharmacokinetics significantly.     

Determination of lamotrigine simultaneously with carbamazepine,carbamazepine epoxide,phenytoin, phenobarbital,and primidone in human plasma by SPME-GC-TSD

A simple and rapid analytical method is presented for the determination of lamotrigine simultaneously with primidone, carbamazepine, carbamazepine epoxide, phenobarbital, and phenytoin in human plasma using solid-phase microextraction (SPME) and gas chromatography with thermionic specific detection. The best conditions for the SPME procedure is established as following: direct extraction on a 65-microm Carbowax-divinylbenzene fiber; 1.0 mL of a sample plasma matrix modified with 15% NaCl and 3 mL of a potassium phosphate buffer (pH 7.0); extraction temperature at 30 degrees C; and stirring at a rate of 2500 rpm for 15 min. The method shows good linearity between 0.05 and 40.0 microg/mL with regression coefficients ranging between 0.9965 and 0.9995 and a coefficient of variation of the points of the calibration curve lower than 10%. The lowest limit of quantitation for the plasma-investigated drugs varies from 0.05 to 0.20 microg/mL, according to the drug. The proposed method is sensitive enough to work into subtherapeutic and therapeutic concentrations, being that it is applied in pharmacokinetic studies and patient routine therapeutic drug monitoring.     

Micromethod for the simultaneous analysis of phenobarbital,diphenylhydantoin, carbamazepine,and primidone in blood

We describe a simple, sensitive method for the determination of phenobarbital, diphenylhydantoin, carbamazepine, and primidone in whole blood by use of gas-liquid chromatography with temperature programming. The methylated derivatives of these anticonvulsants are well resolved. 5-(p-Methylphenyl)-5-phenylhydantoin was used as the internal standard. The proposed procedure requires only 100 μl of blood, which can be collected by finger stick. The lower limit of detection for each of the drugs is 0.5 mg/l. Analytical recoveries of drug from serum were excellent and standard curves were linear to twice the toxic concentration for serum.     

Interaction of surface-active drugs in rabbits

The interaction of chlorpromazine and promethazine in vivo has been investigated. The drugs were administered to the rabbit orally as a single dose (100 mg of each drug) as well as simultaneously with an interval of 15 min. The presence of multiple peaks at the separate administration of promethazine and chlorpromazine on the one hand, and increase of number of peaks, symbathic character of kinetic curves of mentioned drugs and its prolonged appearance in the systemic circulation of the blood by simultaneous administration on the other hand, may be explained by the intensive presystem metabolism and surface-activity ability of these drugs, and by the periodic 'lassitude' of liver for their capture and elimination (either presystem or systemic). The micelle formation from these drugs in the gastro-intestinal tract and formation of the mixed micelles on simultaneous administration were also taken into consideration. Chlorpromazine is more strongly captured by the liver at its first pass through it than promethazine, from comparison of pharmacokinetics of these drugs administered separately. Therefore, chlorpromazine on simultaneous administration occupies the sites of the liver which were covered by promethazine at single dose, thereby substituting promethazine and promoting its transferral into the systemic blood circulation. This results in a large increase in promethazine content in blood, additional peaks appear and the presence of promethazine in the blood is prolonged. The influence of chlorpromazine on the kinetics of promethazine is especially obvious when chlorpromazine enters the organism first and more easily occupies those sites in the liver which participate in the capture and elimination of both drugs. Concerning influence of promethazine on the kinetics of chlorpromazine, promethazine reinforces in some way the ability of liver to capture chlorpromazine, thereby intensifying the presystem metabolism of chlorpromazine and inhibiting its own metabolism. The analogous effect was observed in the study of the influence of promethazine on the kinetics of carbamazepine.     

高效液相色谱法同时测定血清中茶碱、苯妥英钠、苯巴比妥及卡马西平的药物浓度

 报道了用高效液相色谱法（HPLC）同时测定血清中茶减、苯妥莫纳、苯巴比妥及卡马西平的药物浓度。实验条件:Nova-PahC18柱，流动相为甲醇-水（1:1，V／V），检测波长210nm，流速为1mL／min，萃取液为级访-异丙醇（95:5，V／V）。方法具有灵敏（10-9）、准确（回收率在97％～105％之间）、快速（7min）等特点，对临床血药浓度监测有实际应用价值。     

Direct serum injection high-performance liquid chromatographic method for the simultaneous determination of phenobarbital, carbamazepine and phenytoin

A method is described for the simultaneous measurement of serum levels of three antiepileptic drugs, phenobarbital, phenytoin and carbamazepine, by direct injection high-performance liquid chromatography on a 25-cm Pinkerton internal surface reversed-phase (ISRP) column. Several commonly available compounds were tested and found not to co-chromatograph with the three drugs of interest or the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin. Results obtained on patients' samples with this method compared well with those from enzyme-multiplied immunoassay technique (EMIT).     

High-performance liquid chromatographic determination of carbamazepine and carbamazepine 10,11-epoxide in plasma and saliva following solid-phase sample extraction

A rapid, sensitive and simple to operate high-performance liquid chromatographic method for the simultaneous determination of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-EP) in plasma and saliva is described. The drug and its metabolite are extracted from both plasma and saliva using commercially available reversed-phase octadecylsilane bonded silica columns (Bond-Elut C18, 2.8 ml capacity). Separation of CBZ and CBZ-EP was achieved by reversed-phase chromatography, using a mobile phase consisting of acetonitrile-methanol-water (19:37:44) at a flow-rate of 1.8 ml/min in conjunction with a Nova-Pak C18 column. The analytical column, in Radial-Pak cartridge form, was used in combination with a Z-module RCSS and protected by a Guard-Pak precolumn module containing a Guard-Pak mu Bondapak C18 insert. Using ultraviolet detection at 214 nm, levels in the region of 50-100 ng/ml for CBZ and CBZ-EP can be measured with only 250 and 500 microliters of plasma and saliva, respectively. The method, which has been used to determine steady-state concentrations of the drug and its metabolite in paediatric patients receiving CBZ monotherapy, is also suitable for pharmacokinetic studies.     

Application of thermospray liquid chromatography-mass spectrometry to the simultaneous quantification of tracer concentrations of isotopically labelled carbamazepine epoxide and steady-state levels of carbamazepine and carbamazepine epoxide

A thermospray high-performance liquid chromatography-mass spectrometry method for the separation and quantification of tracer concentrations of isotopically labelled carbamazepine epoxide ([15N, 13C]CBZE) in the presence of steady-state levels of the anticonvulsant carbamazepine (CBZ) and its epoxide metabolite (CBZE) has been developed. The technique does not require derivatization, demonstrates little or no thermal degradation of the analytes, provides increased specificity not available from conventional high-performance liquid chromatography, and has a detection limit of 500 pg for CBZE on-column. The method, incorporating d4-CBZ and d4-CBZE as internal standards, allows precise and accurate determination of the analytes with good reproducibility and stability.     

荷移反应分光光度法测定苯巴比妥钠

采用分光光度法研究了电子给体苯巴比妥钠与π电子受体茜素红的荷移反应,建立了荷移分光光度法测定苯巴比妥钠的方法。在水溶液中,苯巴比妥钠与茜素红荷移络合物的最大吸收波长为530 nm,该络合物的组成为1∶1,表观摩尔吸光系数ε为4.43×103L.mol-1.cm-1,稳定常数为2.30×105。药物质量浓度在5~40 mg/L范围内符合比尔定律,相关系数为0.9996。当苯巴比妥钠浓度为20 mg/L时,10次测定结果的相对标准偏差为1.3%。测定了针剂中的苯巴比妥钠,加标回收率在98.9%~105%之间。     

Solvent inclusion in form II carbamazepine

We report on experimental and theoretical evidence for solvent inclusion in form II carbamazepine (R3) and discuss the implications for the formation and stability of this form.     

Thermal decomposition and non-isothermal decomposition kinetics of carbamazepine

The thermal stability and kinetics of isothermal decomposition of carbamazepine were studied under isothermal conditions by thermogravimetry (TGA) and differential scanning calorimetry (DSC) at three heating rates. Particularly, transformation of crystal forms occurs at 153.75°C. The activation energy of this thermal decomposition process was calculated from the analysis of TG curves by Flynn-Wall-Ozawa, Doyle, distributed activation energy model, ?atava-?esták and Kissinger methods. There were two different stages of thermal decomposition process. For the first stage, E and logA [s^?1] were determined to be 42.51 kJ mol^?1 and 3.45, respectively. In the second stage, E and logA [s^?1] were 47.75 kJ mol^?1 and 3.80. The mechanism of thermal decomposition was Avrami-Erofeev (the reaction order, n = 1/3), with integral form G(α) = [?ln(1 ? α)]^1/3 (α = ～0.1–0.8) in the first stage and Avrami-Erofeev (the reaction order, n = 1) with integral form G(α) = ?ln(1 ? α) (α = ～0.9–0.99) in the second stage. Moreover, ΔH ^≠, ΔS ^≠, ΔG ^≠ values were 37.84 kJ mol^?1, ?192.41 J mol^?1 K^?1, 146.32 kJ mol^?1 and 42.68 kJ mol^?1, ?186.41 J mol^?1 K^?1, 156.26 kJ mol^?1 for the first and second stage, respectively.     

流动注射化学发光分析法测定卡马西平

基于酸性条件下溴化钠对NaIO4-H2O2-卡马西平化学发光反应体系具有明显的增敏作用,结合流动注射技术建立了一种测定卡马西平的新方法.在优化的实验条件下,方法的线性范围为1.0×10-9～8.0×10-6g/mL,检出限为3.6×10-10g/mL,相对标准偏差为2.5％(c=2.0×10-7g/mL,n=11),回收率在98.4％～100.6％间.