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PubMed2000

Carbamazepine for cocaine dependence.

BACKGROUND: Cocaine dependence has become a substantial public health problem, developing a significant number of medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorder, has also been used for treatment of cocaine dependence, although its effectiveness has not been established. OBJECTIVES: To determine whether carbamazapine (CBZ) is effective on the treatment of cocaine dependence. SEARCH STRATEGY: Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; scan of reference list of relevant articles; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of carbamazepine drugs versus placebo on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Odds Ratios, weighted mean difference and number needed to treat were estimated. Qualitative assessments of the methodology of eligible studies were carried out using validated checklists. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Where possible analysis was carried out according to the "intention to treat" principles. MAIN RESULTS: 5 studies were included in the review, with 455 people randomised. No differences were found regarding positive urine sample for cocaine metabolites. Scores on Spielberg State Anxiety Inventory slightly favoured carbamazepine, but didn't reach statistical significance. Dropouts were high in both groups up to 70% in the placebo group. Less dropout occurred in the Carbamazepine group (RR 0.87 95%CI 0.71-1.06). When no retention in treatment was due to side effects no differences were found. The number of participants presenting at least one side effect, reported in Kranzler (1995), was higher in the carbamazepine group (RR 4.33 95% CI 1.45-12.91). REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use of CBZ in the treatment of cocaine dependence. Larger randomised investigation must be considered taking into account that these time-consuming efforts should be reserved for medications showing more relevant and promising evidence.

Anticonvulsants↗
PubMed2004

Interference of carbamazepine and carbamazepine 10,11-epoxide in the fluorescence polarization immunoassay for tricyclic antidepressants: estimation of the true tricyclic antidepressant concentration in the presence of carbamazepine using a mathematical model.

We evaluated effects of carbamazepine and its metabolite, carbamazepine 10,11-epoxide, on the measurement of tricyclic antidepressant (TCA) concentrations in serum using the fluorescence polarization immunoassay (FPIA). We determined apparent TCA concentrations in 30 patients who were receiving carbamazepine but no TCAs. Carbamazepine concentrations ranged from 1.4 to 20.9 microg/mL (5.9-88.4 micromol/L); the observed apparent TCA concentrations ranged from 31.8 to 130.1 ng/mL (113.4-463.9 micromol/L). When aliquots of the drug-free serum pool were supplemented with known concentrations of carbamazepine or its metabolite, we observed significant apparent TCA concentrations using the FPIA; however, interference of carbamazepine was more than 3-fold more than its metabolite. When serum pools prepared from patients receiving TCA but no anticonvulsant medications were supplemented with known amounts of carbamazepine or its metabolite, we observed falsely elevated TCA concentrations. We formulated an equation to calculate the apparent TCA concentration from known carbamazepine concentrations. If carbamazepine and TCAs are present in a specimen, the true TCA concentration can be estimated by subtracting the calculated TCA concentration (due to carbamazepine) from the observed TCA concentration as measured by the TCA FPIA. This mathematical modeling is feasible because TCAs, even at very high concentrations, showed no interference with the carbamazepine FPIA.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Simultaneous determination of carbamazepine and carbamazepine 10,11-epoxide by using microcolumn HPLC: study of pharmacokinetics of carbamazepine in a volunteer.

A highly-sensitive microcolumn HPLC method for the simultaneous determination of carbamazepine and carbamazepine-10,11-epoxide in human serum and saliva is described. The method was successfully employed for the study of pharmacokinetics of carbamazepine in humans. After oral administration of 100 and 200 mg of carbamazepine to a volunteer, multiple peaks were observed on the kinetic curves. They were symbathic in the serum and saliva. This indicated the presence of multiple peaks which characterize both free and protein-bound fractions of the drug. The existence of multiple peaks on the kinetic curves implies that the kinetic of carbamazepine cannot be described with the one-compartment linear model. Nevertheless, each peak was treated within the range of a one-compartment linear model of absorption and the results obtained were compared with published data. For the elucidation of the nature of multiple peaks the graphical differentiation of ascending and descending branches of all peaks were carried out. On this basis of the dependence of the absorption and elimination rates on time was constrained. The analysis of experimental data resulted in the following conclusions: (a) the presence of multiple peaks on the kinetic curves is induced by the interrupted character of carbamazepine absorption that is caused by the very poor solubility of carbamazepine; (b) the elimination of the drug from blood serum occurs in two phases. Binding of carbamazepine with tissues takes place in the first phase, and biotransformation and excretion occurs in the second phase. It is possible that the presence of multiple peaks on the kinetic curves is partially caused also by redistribution of the drug from the comparatively easily accessible to the less accessible tissues. This requires further investigation.

Anticonvulsants↗
PubMed1996

Relationships between carbamazepine-diol, carbamazepine-epoxide, and carbamazepine total and free steady-state concentrations in epileptic patients: the influence of age, sex, and comedication.

Steady-state plasma carbamazepine (CBZ), carbamazepine-epoxide (CBZE), and carbamazepine-diol (CBZD) concentrations were quantified by high-performance liquid chromatography in 435 specimens divided into two groups: CBZ monotherapy (n = 78) and CBZ polytherapy (n = 357). Distributions of concentrations of CBZ and its metabolites were derived, their protein binding investigated, and the differences of concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of sex, age, and comedication on CBZ metabolism. Concentrations of CBZ ranged from 2.5 to 82.9 mumol/L (mean +/- SD, 22.3 +/- 10.9 mumol/L), 73% being within the therapeutic range (17-51 mumol/L), 24% being less than the therapeutic range, and 3% greater than the therapeutic range. Concentrations of CBZE ranged from 0.85 to 16.6 mumol/L (mean +/- SD, 5.17 +/- 2.56 mumol/L), and those of CBZD were between 0.77 and 36.4 mumol/L (mean +/- SD, 11.3 +/- 5.4 mumol/L). A multiplicative regression best fitted the concentration/dose plots of CBZ and CBZE and an exponential regression for CBZD. Dose correlated best with the second biotransformation product, CBZD. Free fractions were 0.22 +/- 0.03 for CBZ, 0.40 +/- 0.06 for CBZE, and 0.68 +/- 0.11 for CBZD. Sex was found to be of minor importance for CBZ disposition. A gradual, high-amplitude age increase of CBZ dose ratio was observed in the monotherapy group, with global difference of approximately 3.6 times, while CBZE dose ratio increased approximately 2-fold, and CBZD dose ratio increased to the smallest extent of 1.5 times. In the polytherapy group, a smaller global age increase for CBZ dose ratio of 3.4 times was found, but the respective increase for dose ratios of metabolites was greater compared with the monotherapy patients: 2.3 times for CBZE and 1.8 times for CBZD. Comedication of other antiepileptic drugs induced significant decrease of CBZ dose ratio only, but no changes of dose ratios of the metabolites were registered. The influence of valproic acid was represented in a particular pattern. We conclude that these findings could provide valuable information for CBZ metabolism and disposition in epileptic patients with respect to the efforts to ensure the best possible individualization of CBZ therapy.

Adolescent↗
PubMed1989

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.

Carbamazepine↗
PubMed2003

Patch testing with carbamazepine and its main metabolite carbamazepine epoxide in cutaneous adverse drug reactions to carbamazepine.

The value of skin tests in the diagnosis of adverse drug reactions (ADRs) has been limited. Lack of knowledge as to the nature of drug allergens has contributed to these limitations. Several reports have addressed the roles of metabolites in cutaneous ADRs and skin testing. We evaluated the role of a carbamazepine (CBZ) metabolite on the results obtained from patch tests, using CBZ and its main metabolite 10, 11-epoxide of CBZ (CBZ-epoxide), on 13 patients with CBZ-induced drug eruptions and 39 controls with no CBZ-induced cutaneous ADRs. 10 of the 13 patients showed a positive reaction, and 2 of the 10 patients had a reaction to the CBZ-epoxide only and 1 to both CBZ and CBZ-epoxide. None of the 39 controls displayed any reactions to either CBZ or CBZ-epoxide. Patch testing of suspected drugs, as well as their available metabolites, would be helpful in improving the results.

Adolescent↗
PubMed2000

Carbamazepine for schizophrenia and schizoaffective psychoses.

BACKGROUND: A sizeable minority of people with schizophrenia do not have complete remission of symptoms. A variety of adjunctive treatments have been used to treat schizophrenia, carbamazepine being one. OBJECTIVES: To review the effects of carbamazepine and its derivatives for the treatment of schizophrenia and schizoaffective psychoses. SEARCH STRATEGY: Biological Abstracts (1980-1998), The Cochrane Library (Issue 3, 1998), The Cochrane Schizophrenia Group's Register of Trials (August 1998), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1886-1998) and PSYNDEX (1974-1998) were searched. Citations from included trials were also inspected and relevant companies and authors contacted for additional data. SELECTION CRITERIA: All randomised controlled trials comparing carbamazepine, or compounds of the carbamazepine family, to placebo or no intervention, whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizoaffective psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted independently by at least two reviewers. Dichotomous data were analysed using Peto odds ratio (OR) and the 95% confidence interval (CI) estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics were calculated. MAIN RESULTS: There is no clear effect of carbamazepine as the sole maintenance treatment for those with schizophrenia. Eight trials provided very limited data on the value of carbamazepine as an adjunct to antipsychotics. Studies were small and poorly reported. Currently no published data provides convincing evidence that adjunctive carbamazepine has an effect on global functioning, mental state, side effects or acceptability of treatment. REVIEWER'S CONCLUSIONS: Based on currently available randomised trial-derived evidence, carbamazepine cannot be recommend for routine clinical use for treatment or augmentation of antipsychotic treatment of schizophrenia. However, for those with a past history of being responsive to carbamazepine, or for those with associated EEG abnormalities, a trial of the drug may be warranted. More data is expected from trialists and the results of this review may be changed by their inclusion. At present large, simple well designed and reported trials are justified especially if focusing on those with both schizophrenia and EEG abnormalities or violent episodes and people with schizoaffective disorders.

Antimanic Agents↗
PubMed2001

Determination of carbamazepine and its metabolite carbamazepine-10,11-epoxide in serum with gas-chromatography mass spectrometry.

Carbamazepine, one of the most often used antiepileptic drugs, undergoes enzyme biotransformation through epoxidation with the formation of its metabolite, carbamazepine-10,11-epoxide (carbamazepine epoxide). The determination of carbamazepine epoxide is clinically significant in therapeutic drug monitoring as it decreases the risk of toxic reactions and increases the possibility of reaching the expected therapeutic result. The aim of this study was to introduce a gas chromatographic method with mass spectrometric detection to simultaneously determine the serum levels of carbamazepine and carbamazepine epoxide. Blood samples from 80 epileptic patients aged between 1 and 63 years were analyzed. All patients were taking carbamazepine as monotherapy and had achieved the steady state serum drug concentration. A microcolumn extraction of carbamazepine and carbamazepine epoxide was obtained by elution. A gas chromatograph with a mass spectrometer and a 25 m x 0.2 mm ID, 0.33 micron film thickness, crosslinked 5% phenyl-methylsilicone capillary column HP-5 was used. The coefficients of correlation for the calibration plots obtained for carbamazepine epoxide and carbamazepine were 0.988 and 0.995, respectively. The precision, tested for n = 20, showed coefficients of variation within one day as follows: carbamazepine epoxide: 11.0% and 6.55%; carbamazepine: 11.8% and 5.4%. The coefficients of variation from day to day were: carbamazepine epoxide: 9.4% and 6.83%; carbamazepine: 8.5% and 5.7%. The detection limit was 10 micrograms/l and the recovery 82.5% for carbamazepine epoxide and 92.5% for carbamazepine. A fast and simple gas chromatographic method for the routine therapeutic monitoring of carbamazepine and carbamazepine epoxide was developed. The simultaneous determination of the serum levels of carbamazepine epoxide and carbamazepine offers the possibility of measuring the total drug concentration, as well as that of its metabolite, while considering the results of clinical response and the special features of carbamazepine's enzymatic biotransformation through epoxidation with the formation of its metabolite.

Adolescent↗
PubMed1986

Total and free serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in children with epilepsy.

Simultaneous steady-state serum total and free (non-protein-bound) concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured in 68 patients under the age of 21 years with epilepsy (44 males, 24 females; mean age, 11.8 +/- 4.5 years). Thirty patients were maintained on monotherapy with carbamazepine. Mean serum total carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 7.0 +/- 2.4 mg/L (29.5 +/- 10.0 mumol/L) and 1.5 +/- 0.6 mg/L (5.9 +/- 2.6 mumol/L), respectively. Mean serum-free carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 1.3 +/- 0.5 mg/L (5.7 +/- 2.1 mumol/L) and 0.5 +/- 0.3 mg/L (2.2 +/- 1.1 mumol/L), respectively. Binding of carbamazepine and carbamazepine-10,11-epoxide was 81% +/- 3% and 62% +/- 10%, respectively. There was no significant difference in binding between male and female patients or those maintained on monotherapy and polytherapy. Age correlated significantly with carbamazepine binding but not with carbamazepine-10,11-epoxide binding. Free concentrations of carbamazepine and carbamazepine-10,11-epoxide correlated significantly with total carbamazepine and total carbamazepine-10,11-epoxide concentrations, respectively, indicating that the binding capacities of both carbamazepine and carbamazepine-10,11-epoxide are constant at serum total carbamazepine concentrations within the quoted therapeutic range.

Adolescent↗
PubMed2002

Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide.

Carbamazepine (amizepine) is a widely used psychotropic agent. A much easier accessibility of this drug, observed during the recent years, may account for an increasing number of acute intoxications with carbamazepine. The aim of this study was to determine the elimination kinetics of carbamazepine and its metabolite carbamazepine 10,11-epoxide, and to identify the quantitative relationship between concentrations of these compounds, in serum. The subjects were 41 patients with acute carbamazepine intoxication. Serum carbamazepine and carbamazepine 10,11-epoxide concentrations were determined every 6 hours during thefirst 24 hours of hospitalization, and then every 12 hours. At the same time, urinalyses were performed for each patient to confirm or exclude homogeneity of poisoning. Depending on the type of intoxication (homogenous or combined), three groups of patients, and on the method of treatment (symptomatic, charcoal administration), two groups of patients were distinguished. The statistical analysis of the results revealed that among the investigated parameters (time-integrated concentrations of carbamazepine and carbamazepine 10,11-epoxide in serum, the presence of drugs, and/or ethanol, charcoal treatment) only carbamazepine concentrations had statistically significant effect on the duration of coma regarded as a critical effect. The kinetics of carbamazepine elimination was determined on the basis of the mean carbamazepine concentrations at the same timing of sampling for each patient in all the three groups; the mean carbamazepine elimination in serum followed zero-order kinetics. In individual groups, the decrease in serum carbamazepine concentrations ranged from 0.5 to 0.8 mg L(-1) hour(-1). Contrary to the suggestions found in the literature, carbamazepine 10,11-epoxide determination does not seem to enhance the possibility of anticipating the course of intoxication or the time of recovery.

Adult↗
PubMed2006

Activation of T cells by carbamazepine and carbamazepine metabolites.

BACKGROUND: T-cell-mediated hypersensitivity is a rare but serious manifestation of drug therapy. OBJECTIVES: To explore the mechanisms of drug presentation to T cells and the possibility that generation of metabolite-specific T cells may provoke cross-sensitization between drugs. METHODS: A lymphocyte transformation test was performed on 13 hypersensitive patients with carbamazepine, oxcarbazepine, and carbamazepine metabolites. Serial dilution experiments were performed to generate drug (metabolite)-specific T-cell clones to explore the structural basis of the T-cell response and mechanisms of antigen presentation. 3-Dimensional energy-minimized structures were generated by using computer modeling. The role of drug metabolism was analyzed with 1-aminobenzotriazole. RESULTS: Lymphocytes and T-cell clones proliferated with carbamazepine, oxcarbazepine, and some (carbamazepine 10,11 epoxide, 10-hydroxy carbamazepine) but not all stable carbamazepine metabolites. Structure activity studies using 29 carbamazepine (metabolite)-specific T-cell clones revealed 4 patterns of drug recognition, which could be explained by generation of preferred 3-dimensional structural conformations. T cells were stimulated by carbamazepine (metabolites) bound directly to MHC in the absence of processing. The activation threshold for T-cell proliferation varied between 5 minutes and 4 hours. 1-Aminobenzotriazole, which inhibits cytochrome P450 activity, did not prevent carbamazepine-related T-cell proliferation. Substitution of the terminal amine residue of carbamazepine with a methyl group diminished T-cell proliferation. CONCLUSION: These data show that carbamazepine and certain stable carbamazepine metabolites stimulate T cells rapidly via a direct interaction with MHC and specific T-cell receptors. CLINICAL IMPLICATIONS: Some patients with a history of carbamazepine hypersensitivity possess T cells that cross-react with oxcarbazepine, providing a rationale for cross-sensitivity between the 2 drugs.

Adult↗
PubMedDate not supplied

Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update.

Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 mumol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1982

Routine monitoring of carbamazepine and carbamazepine-10,11-epoxide in plasma by high-performance liquid chromatography using 10-methoxycarbamazepine as internal standard.

Carbamazepine and carbamazepine-10,11-epoxide were separated by high-performance liquid chromatography (HPLC) with acetonitrile-water as mobile phase, and detection was effected by UV absorption at 215 nm with a total retention time of less than 10 min. Plasma samples were extracted with dichloromethane and 4 M sodium hydroxide, and 10-methoxy-carbamazepine was added as internal standard. Other commonly used anticonvulsant drugs present in plasma showed no significant interference. The within-batch coefficient of variation for carbamazepine was 4.9% and carbamazepine-10,11-epoxide 5.9%. Between-batch coefficients of variation were 3.7% and 5.3%, respectively. Mean recovery for carbamazepine was 100.2% and for carbamazepine-10,11-epoxide 100.6%. This HPLC method was compared with both an enzyme immunoassay procedure (EMIT) and a gas-liquid chromatographic (GLC) method. Correlation coefficient between HPLC/EMIT for carbamazepine was 0.983, HPLC/GLC carbamazepine 0.988 and HPLC/GLC carbamazepine-10,11-epoxide 0.981.

Carbamazepine↗
PubMed1977

Measurement of carbamazepine and its epoxide metabolite by high-performance liquid chromatography, and a comparison of assay techniques for the analysis of carbamazepine.

We describe a modified high-performance liquid-chromatographic method for the simultaneous analysis of carbamazepine andits biologically active metabolite, carbamazepine-10, 11-epoxide. Concentrations of both these compounds in the plasma of 35 epileptic patients receiving chronic carbamazepine therapy are presented. Concentrations of carbamazepine in plasma were related to those of carbamazepine-10, 11-epoxide (r - 0.495, P less than 0.05). Total daily doses of carbamazepine were better correlated with plasma concentrations of carbamazepine-10, 11-epoxide (r = 0.714, P less than 0.001) than of carbamazepine (r = 0.269, P greater than 0.05). Close correlations were found between results of the three assay procedures we used to measure plasma carbamazepine concentrations: high-performance liquid chromatography, gas-liquid chromatography, and enzyme immunoassay. Correlation coefficients exceeded 0.97 and regression slopes were near unity, indicating that all three procedures were individually specific for the quantification of plasma carbamazepine.

Carbamazepine↗
PubMed1981

Induction effect of phenobarbital on the carbamazepine to carbamazepine-10, 11-epoxide pathway in rhesus monkeys.

The induction effect of phenobarbital on the carbamazepine to carbamazepine-10, 11-epoxide pathway was investigated in seven rhesus monkeys. Each animal received an 8-hr infusion of carbamazepine on days 1, 5 and 15. In addition, animals received an acute dose (130 mg) of phenobarbital on day 5 followed by 10 daily maintenance doses (40 mg). Plasma samples were assayed for phenobarbital, carbamazepine and epoxide by gas chromatography interfaced with a mass spectrometer in chemical ionization mode. The control mean +/- S.D. values of plasma clearance, volume of distribution and T1/2 for carbamazepine were 7.3 +/- 2.37 liters/hr, 9.61 +/- 2.29 liters and 0.96 +/- 0.02 hr, respectively. The control steady-state ratio of epoxide to carbamazepine was 0.065 +/- 0.023. An acute loading dose of phenobarbital caused an apparent decrease in clearance (6.05 +/- 1.80 liters/hr, P = .06) with no apparent changes in other parameters. Subchronic administration of phenobarbital resulted in increases in clearance (14.42 +/- 4.91 liters/hr, P = .006) and volume distribution (12.00 +/- 2.06 liters, P = .01), a decrease in T1/2 (0.62 +/- 0.15 hr, P = .006) and an apparent increase in the epoxide to carbamazepine steady-state ratio (0.085 +/- 0.013, P = .06). The increase in the epoxide to carbamazepine ratio after subchronic administration of phenobarbital suggests that phenobarbital induces the formation of epoxide more than its elimination. This is in direct contrast to the lowering of the epoxide to carbamazepine ratio by carbamazepine autoinduction.

Animals↗
PubMed1994

In vivo binding characteristics of carbamazepine and carbamazepine 10, 11-epoxide to serum proteins in monotherapy adult patients.

The in vivo serum protein binding characteristics of carbamazepine and carbamazepine 10, 11-epoxide, which was the main metabolite of carbamazepine in plasma, were assessed in sera from 30 adult patients with epilepsy on carbamazepine monotherapy. The binding characteristics of each compound were analyzed according to the two-site binding model. Association constants to the high-affinity binding site on alpha 1-acid glycoprotein (AAG) were 0.053 l/mumol for carbamazepine and 0.013 l/mumol for carbamazepine 10, 11-epoxide. The maximum binding capacities for drug-AAG binding were 49.2 mumol/l for carbamazepine and 48.1 mumol/l for carbamazepine-10, 11-epoxide. The products of the association constant and binding capacity for the lower-affinity site (i.e., the linear component of albumin binding site) were 1.273 for carbamazepine and 0.525 for carbamazepine 10, 11-epoxide. Within the total concentration range of each compound investigated, the contribution of drug-AAG binding to the total serum binding was relatively larger than that of drug-albumin binding.

Adolescent↗
PubMed2005

Analytic performance evaluation of a new turbidimetric immunoassay for carbamazepine on the ADVIA 1650 analyzer: effect of carbamazepine 10,11-epoxide.

Carbamazepine, an anticonvulsant, requires therapeutic drug monitoring. Recently Bayer HealthCare, Diagnostics Division released a turbidimetric immunoassay of carbamazepine on the ADVIA 1650 analyzer. We evaluated the analytic performance of this assay by comparing values obtained with this new assay in sera of 54 patients receiving carbamazepine with the values obtained by using a widely used fluorescence polarization immunoassay (FPIA) and a chemiluminescent immunoassay (CLIA). The new turbidimetric immunoassay for carbamazepine showed excellent precision. The low control showed a total CV of 4.9% (mean 2.86, SD 0.14 microg/mL), the medium control demonstrated a total CV of 3.5% (mean 7.79, SD 0.27 microg/mL), and the high control showed a total CV of 4.8% (mean 16.15, SD 0.78 microg/mL). The assay was linear up to a carbamazepine concentration of 20 microg/mL. The assay showed excellent dilution recovery and recovery of samples supplemented with carbamazepine (mean recovery 102.2%). We observed an excellent correlation between the values obtained by the FPIA (x-axis) assay and the new turbidimetric (y-axis) assay (y = 0.96 x - 0.46, r = 0.99, n = 54). We also observed excellent correlation between the values obtained by the CLIA (x-axis) and the turbidimetric (y-axis) assay (y = 1.10 x -0.32, r = 0.99, n = 54). However, the slope of 1.10 was higher than the slope of 0.96 observed with the regression equation obtained by using values obtained by the FPIA and the turbidimetric assay. The positive bias obtained with the new turbidimetric assay compared with the CLIA assay resulted from lower cross reactivity of carbamazepine 10,11-epoxide, the active metabolite of carbamazepine, with CLIA. On the other hand, the cross reactivity of the metabolite is similar between the new turbidimetric assay and the FPIA assay. We conclude that the new turbidimetric assay can be used for routine monitoring of carbamazepine in clinical laboratories.

Carbamazepine↗
PubMed1984

Determinants of carbamazepine and carbamazepine 10,11-epoxide binding to serum protein, albumin and alpha 1-acid glycoprotein.

The binding of carbamazepine and carbamazepine 10,11-epoxide to serum, albumin and alpha 1-acid glycoprotein (AAG) was determined and compared at drug concentrations ranging from 0.5 to 400 mg/l using equilibrium dialysis and liquid chromatography. The total binding of carbamazepine in serum was determined primarily by albumin and to a lesser extent (20-30%) by AAG. Modified Scatchard plots for carbamazepine binding in serum were biphasic, suggesting the presence of two binding sites on serum protein. Association constants characterizing the first (k1 = 2.4 X 10(4) l/mol) and second (k2 = 4.6 X 10(2) l/mol) binding sites agreed with those measured for AAG and albumin respectively. Modified Scatchard plots for carbamazepine 10,11-epoxide binding in serum were linear and serum binding was largely accounted for by binding to albumin. The epoxide metabolite did not bind to AAG. Carbamazepine binding to AAG was drug concentration-dependent over the concentration range considered to be therapeutic, while the percent binding values for carbamazepine and epoxide binding to albumin and serum from a normal individual were constant over this range. Computer simulations showed that physiological extremes in AAG and albumin concentrations can result in a range of carbamazepine unbound fractions of 0.17 to 0.47. These data suggest that normal variations in concentrations of both proteins may be the principal cause of interpatient variability in serum protein binding of carbamazepine.

Blood Proteins↗