Serum Carbamazepine Concentration Research Articles

Evaluation of carbamazepine and carbamazepine-epoxide protein binding in patients undergoing epilepsy surgery.

Carbamazepine (CBZ) serum concentrations increase after epilepsy surgery. A possible mechanism may be acute changes in protein binding, specifically those involving the acute phase reactant alpha(1)-acid glycoprotein (AAG). We prospectively evaluated 16 adults (11 receiving CBZ) with epilepsy (mean age 30 +/- 9.9 years, 8 women and 8 men) undergoing temporal lobe resections and characterized AAG, albumin, CBZ, and CBZ-epoxide (CBZ-E) free fractions over time. AAG, ALB, CBZ, and CBZ-E free fractions were determined before surgery (baseline) and on postoperative days 1-5, 14, and 30. AAG was measured with a radial immunodiffusion assay method, CBZ and CBZ-E serum concentrations were determined by high-performance liquid chromatography (HPLC). Free fractions of CBZ and CBZ-E were calculated as the ratio of unbound (determined after ultracentrifugation) to total serum drug concentrations. Statistical analysis included analysis of variance (ANOVA) and Student's t test for paired data when appropriate, with significance assigned at p<0.05. All data are mean +/- SD. AAG concentrations increased significantly from baseline 61.9 +/- 21.3 mg/dl), peaking at postoperative day 3 (116.8 +/- 20.6 mg/gl) and decreasing to baseline levels between days 14 and 30. CBZ serum concentrations were significantly increased in the immediate postoperative period (day 3), but albumin concentrations and CBZ and CBZ-E free fractions did not differ significantly between baseline and the postoperative time points. Temporal lobe resection results in an acute phase reaction which is manifested in part by significant changes in AAG. Although CBZ and CBZ-E total serum concentrations increased significantly in the immediate postoperative period, epilepsy surgery did not appear to result in significant overall changes in drug binding to plasma proteins.

Quantitative pharmaco-EEG of carbamazepine in volunteers and epileptics.

In order to measure the effect of carbamazepine (CBZ) on quantitative EEG (qEEG), one dose of CBZ (300 mg) was administered to 10 epileptics and 10 healthy adult volunteers. EEG samples were recorded before and at regular intervals within 24 hours following administration. The EEG activity was processed by power spectral analysis and the drug serum concentration was assessed concomitantly. The results showed that with the increase of serum concentration of CBZ, the percentage of power progressively increased in the theta band while it decreased in the alpha 2 band. The percentage of theta and alpha 2 power was found to reach maximum and minimum levels, respectively, when the peak values of serum concentration of CBZ were attained. The effects on qEEG in anterior scalp areas were more evident than in posterior scalp areas.

Cerebral and cerebellar diaschisis following carbamazepine therapy

1. 1. The regional cerebral blood flow was studied by SPECT in patients with partial epilepsy before and after 30 days of monotherapy with carbamazepine (CBZ). 2. 2. Both a qualitative visual interpretation and a semiquantitative analysis of SPECT was performed. All patients underwent EEG, CT scan, and MRI studies. The CBZ serum concentrations were assayed. 3. 3. After therapy, in three patients with focal epilepsy, both a crossed cerebral and cerebellar diaschisis were observed, with respect to the side of the epileptic focus in the opposite hemisphere. No morphologic changes were detected at MRI in the cerebral or cerebellar remote hypometabolic areas found at SPECT. 4. 4. CBZ may have a depressant action on the corticopontocerebellar pathways and on the corticocallosal connections.

Evaluation of Equations for Unbound Serum Concentration Prediction of Carbamazepine and Carbamazepine-10,11-epoxide in Polytherapy Pediatric Patients with Epilepsy

We retrospectively evaluated the ability of equations with in vivo population binding parameters of our previous study (Method 1) or an average unbound fraction of 0.25 of Pynnönen (Method 2) to predict the unbound serum carbamazepine (CBZ) concentration in 50 serum samples from 28 polytherapy pediatric patients with epilepsy. In 12 serum samples from 10 patients, the ability of equations for unbound serum carbamazepine-10,11-epoxide (CBZ-E) concentration prediction was also determined in predictive performance with in vivo population binding parameters of our previous study (Method A) or an average unbound fraction of 0.5 of Pynnönen (Method B). Mean prediction error, mean absolute prediction error (MAE), and root mean squared error (RMSE) were calculated for each method, and these values served as a measure of prediction bias and precision. Method 1 shows a bias to underpredict unbound serum CBZ. The MAE and RMSE were lower in Method 2 (MAE = 0.696, μm, RMSE = 0.912 μM) than in Method 1 (MAE = 0.946 μM, RMSE = 1.138 μM). Method 2 is superior to Method 1 in accuracy and precision. The effects of antiepileptic co-medications on predictive performance of Method 1 are relatively larger in a co-medicated group of serum samples with valproic acid(n= 33, MAE = 0.994 μM, RMSE = 1.211 μM) than in a group of serum samples without valproic acid co-medication (n= 17, MAE = 0.853 μM, RMSE = 0.979 μM). Furthermore, the effects of the number of antiepileptic co-medications on predictive performance of Method 1 are relatively smaller in a group of serum samples of CBZ with one co-medication (n=17, MAE = 0.600 μM, RMSE = 0.682 μM) than in each group of those of CBZ with two (n= 16, MAE = 1.219 μM, RMSE = 1.378 μM) and with three to six co-medications (n= 17, MAE = 1.035 μM, RMSE = 1.246 μM). For unbound CBZ-E prediction, Method B has a bias to overprediction. The MAE and RMSE were lower in Method A (MAE = 0.267 μM, RMSE = 0.354 μM) than in Method B (MAE = 0.400μM, RMSE = 0.517 μM). Method A is superior to Method B in accuracy and precision.

Cardiovascular Effects of Carbamazepine Toxicity

Study objective: To evaluate the cardiovascular effects of carbamazepine in patients presenting to the emergency department. Design: A retrospective case series from February 1, 1985, to July 30, 1993. Setting: Six urban EDs. Participants: Seventy-two adult and pediatric patients with serum carbamazepine concentrations greater than 12 μg/ml and concurrent 12-lead ECGs. Results: The mean carbamazepine level was 24 μg/ml (range, 12.6 to 55 μg/ml). Minor ECG abnormalities were noted but no clinically significant arrhythmias were found. No correlation was found between carbamazepine concentration and heart rate or PR, QRS, or corrected QT intervals. Four adult patients had transient hypotension. Conclusion: Clinically significant cardiovascular toxicity occurs rarely in patients with toxic carbamazepine concentrations. ECG findings do not correlate with serum carbamazepine concentration. [Apfelbaum JD, Caravati EM, Kerns WP II, Bossart PJ, Larsen G: Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med May 1995;25:631-635.]

The influence of polytherapy on the relationships between serum carbamazepine and its metabolites in epileptic children

The influence of polytherapy on the relationships between the age, weight, carbamazepine (CBZ) dose, total clearance and intrinsic clearance, with concentrations, concentration ratios and level/dose ratios of CBZ, carbamazepine-10,11-epoxide (CBZ-E) and trans-10,1 l-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) are investigated. Three groups of patients with CBZ monotherapy, or receiving CBZ polytherapy by taking CBZ and valproic acid (VPA) or CBZ plus other antiepileptic drugs (AEDs) were studied. The significant correlations between serum CBZ concentrations and CBZ dose in patients taking CBZ alone were no longer significant in patients with polytherapy and the positive associations between serum CBZ-E concentrations and CBZ dose were lost in patients with CBZ + VPA. Only the concentrations of CBZ-H had significant correlations with CBZ dose in all three groups of patients. Results from this relationship study indicate a heteroinduction effect of other AEDs on CBZ metabolism and a relatively weak influence on CBZ-E elimination. Data also suggest that there is a block in the biotransformation from CBZ-E to CBZ-H in patients taking CBZ + VPA, presumably caused by the inhibition effect of VPA on epoxide hydrolase. Therapeutic drug monitoring of CBZ will benefit from the knowledge obtained from the relationship study.

血清中カルバマゼピン濃度に及ぼすフェニトインおよびバルプロ酸併用の影響

血清中カルバマゼピン濃度に及ぼすフェニトインおよびバルプロ酸併用の影響

Concentrations of Carbamazepine and Carbamazepine-10,11-Epoxide in Serum, Brain Tumors and Paratumorous Cortex: A Prospective Study of 37 Neurosurgically Treated Epileptic Patients

Concentrations of carbamazepine (CBZ) and its metabolite carbamazepine-10, 11-epoxide (CE) were determined in serum (free and total), brain tumors and paratumorous cortex from 37 epileptic patients. Tumor biopsies were available from 25 different gliomas, 5 hamartomas and 1 angioma. The free serum concentrations of CBZ and CE were highly correlated with the corresponding paratumorous concentrations (r = 0.94 and r = 0.93) and to a lower extent with the tumorous concentrations (r = 0.78 and r = 0.75). For CBZ the concentration ratios paratumorous cortex/serum free and tumor/serum free showed no significant differences between CBZ-resistant and -nonresistant patients. Apart from histological grade a significant influence of type and site of the tumors on their CBZ and CE concentration was not recognizable. The results indicate that resistance to CBZ therapy cannot be sufficiently explained by decreased paratumorous or tumorous levels of CBZ and CE.

Long-term observation of the relation between pain intensity and serum carbamazepine concentration in elderly patients with trigeminal neuralgia

The relation between changes in pain intensity and serum carbamazepine (CBZ) concentration was studied in five elderly patients with trigeminal neuralgia. Measurement of pain intensity and serum CBZ concentration, and blood studies, were performed approximately every 2 or 3 months after initiation of CBZ therapy. Fluctuations in pain intensity were observed in four patients. In these patients, even when the serum CBZ concentration was maintained within a relatively high range, there were periods in which pain intensity increased. On the other hand, there were periods in which pain was relatively well controlled even though the CBZ concentration was relatively low. There were considerable interindividual differences in response to CBZ. The fluctuations in pain showed that the CBZ response curve varies from period to period even within an individual. It was concluded that it is essential to observe spontaneous variations in pain intensity and monitor serum CBZ during long-term administration.

Long-term observation of the relation between pain intensity and serum carbamazepine concentration in elderly patients with trigeminal neuralgia

Long-term observation of the relation between pain intensity and serum carbamazepine concentration in elderly patients with trigeminal neuralgia

Determination of Total and Free Carbamazepine and the Principal Metabolites in Serum by High-Performance Liquid Chromatography with Photodiode-Array Detection

A precise and accurate high-performance liquid chromatography (HPLC) method has been established for the simultaneous analysis of carbamazepine (CBZ), carbamazepine-10,11-epoxide (CBZ-E), and trans-10,11-dihydroxy-10,11-dihydro-CBZ (CBZ-H) in serum samples and their ultrafiltrates. CBZ and its metabolites are eluted in a 3-microM ODS-Hypersil column (250 x 2 mm) at a column temperature of 40 degrees C. The mobile phase is a mixture containing potassium phosphate buffer-acetonitrile-methanol (110:50:30, vol/vol/vol) at a flow rate of 0.2 ml/min. Signals are monitored by a photodiodearray detector with a main sample wavelength of 215 nm and a bandwidth of 10 nm. Coefficients of variation (CVs) for within- and between-day are within 5%, with the recovery rates ranging from 98.16 to 104.64%. This method has the necessary sensitivity and linearity for routine therapeutic monitoring of both total and free CBZ and its principal metabolites. Total serum concentrations of CBZ, CBZ-E, and CBZ-H obtained from 55 epileptic children were 12.58 +/- 4.42, 2.45 +/- 1.22, and 5.83 +/- 3.17 (mean +/- SD, micrograms/ml), respectively. Levels of free CBZ, CBZ-E, and CBZ-H were 2.59 +/- 0.93, 1.05 +/- 0.57 and 3.73 +/- 1.87, respectively. Free fractions of CBZ, CBZ-E, and CBZ-H were 20.98 +/- 4.34, 42.63 +/- 8.21, and 65.41 +/- 7.80%, respectively. CBZ-H and CBZ-E had larger CVs than did CBZ (54.34 and 49.75 vs 35.15%, respectively, for total levels, and 50.31 and 54.46 vs 36.22%, respectively, for free levels), as well as higher free fractions. Determination of both total and free concentrations and free fractions of CBZ and its metabolites, as well as their ratios, should provide additional needed information for therapeutic drug monitoring of CBZ.

Unmasking the Significant Enzyme-Inducing Effects of Phenytoin on Serum Carbamazepine Concentrations during Phenytoin Withdrawal

We report on two patients who appeared to exhibit profound induction of carbamazepine metabolism during cotherapy with phenytoin. Gradual withdrawal of phenytoin confirmed this impression. Two case studies. Two patients receiving carbamazepine and phenytoin as combination anticonvulsant therapy were admitted for comprehensive rehabilitation. A 23-year-old man had therapeutic serum phenytoin concentrations, but his serum carbamazepine concentrations were so low that they were nonquantifiable. Doubling the daily carbamazepine dosage did not yield quantifiable serum concentrations. When the daily phenytoin dosage was tapered from 500 to 200 mg, the carbamazepine concentration rose to 10.0 micrograms/mL. No further changes in serum carbamazepine concentrations were observed when the phenytoin was discontinued. A 49-year-old man was receiving large daily dosage of phenytoin (600 mg) and carbamazepine (2300 mg). In the process of tapering and discontinuing phenytoin, the patient became lethargic and confused. These signs and symptoms suggested carbamazepine toxicity. The patient was eventually stabilized on a carbamazepine dosage of 1200 mg/d, which produced a serum concentration of 8.4 micrograms/mL. When this patient had been receiving concurrent phenytoin therapy, approximately twice as much carbamazepine (2300 mg) was required to maintain a similar serum concentration. Phenytoin is a potent inducer of carbamazepine metabolism. Whenever phenytoin dosages are tapered and discontinued in patients receiving these medications concomitantly, frequent serum carbamazepine monitoring is recommended during the ensuing deinduction phase.

Comparative bioavailability of carbamazepine from two slow-release preparations

In order to compare the multiple-dose bioavailability of carbamazepine (CBZ) from 2 slow-release preparations, Neurotol slow and Tegretol Retard, a single-blind, randomized, cross-over study was carried out. 21 adult patients with epilepsy were enrolled in the study. At the end of both 2-week treatment periods, a blood sample series was drawn after the administration of the morning CBZ dose. The serum concentrations of CBZ, CBZ-10,11-epoxide (CBZE) and 10,11-dihydro-10,11- trans-dihydroxy-CBZ (CBZD) were measured using HPLC. The mean bioavailability of CBZ from Neurotol slow was 11% ( P = 0.002) higher than from Tegretol Retard. Owing to the better bioavailability, the peak (C max), lowest (C min) and mean (C ss) concentrations of CBZ were also significantly higher during Neurotol slow treatment. Fluctuation of serum CBZ concentrations (C max-C min/C ss, AD C ss /AUC 0–12h) did not differ significantly between the 2 treatments; neither did t max. Similar results were obtained with CBZE and CBZD. There were more epileptic seizures on Tegretol Retard than on Neurotol slow, but the difference was not statistically significant. We conclude that there are significant differences in the bioavailability of CBZ from these 2 slow-release preparations.

Cognitive functions, epileptic syndromes and antiepileptic drugs.

Cognitive function of patients on monotherapy specific for their epileptic syndrome has been studied infrequently. We evaluated 7 patients with symptomatic localised epilepsies (SEL) on phenytoin aged 30 +/- 12 (mean +/- standard deviation) years, 8 with idiopathic generalised epilepsies on sodium valproate aged 18 +/- 4 years, 16 with SEL on carbamazepine aged 28 +/- 11 years, and 35 healthy controls aged 27 +/- 11 years. All subjects were of normal intelligence, educated appropriately to age, and led productive lives in the community. Two of the patients on carbamazepine and one on valproate had less than five partial, absence or myoclonic seizures monthly, the remaining were controlled. Carbamazepine serum concentrations were 12 +/- 5 micrograms/ml, phenytoin were 23 +/- 7, and valproate were 62 +/- 23 (mean +/- sd). Tests included immediate recall and recognition for pictures, Stroop test, delayed recall and recognition of pictures. Patients on phenytoin and valproate performed significantly worse than controls on immediate recall, and patients on carbamazepine performed significantly worse than controls in Stroop test (p < 0.01). The results indicate relatively minor effects of the epileptic syndromes and of phenytoin, carbamazepine and valproate on cognition of patients with controlled epilepsy leading productive lives in the community. We conclude that the cognitive deficit found in chronic epileptic patients on poly-therapeutic drug regimen must be multifactorial, and that future studies need to control for all possible variables in order to achieve meaningful results.

Rapid tolerance to acute psychomotor impairment with carbamazepine in epileptic patients.

Thirteen patients with newly diagnosed epilepsy performed a battery of psychomotor function tests before and during the first 12 weeks of carbamazepine (CBZ) therapy. Movement time (P less than 0.025), total choice reaction time (P less than 0.025), finger tapping rate (P less than 0.005) and number cancellation (P less than 0.05) were all significantly impaired after 1 week's treatment, but had returned to baseline by 4 weeks. Mean (+/- s.d.) serum CBZ concentrations and those of its active metabolite CBZ 10,11 epoxide (CBZ-E) were comparable at 1 (CBZ: 8.5 +/- 2.1 mg l-1, CBZ-E: 1.1 +/- 0.68 mg l-1) and 4 weeks (CBZ: 8.1 +/- 4.4 mg l-1, CBZ-E: 0.93 +/- 0.27 mg l-1). These results suggest the rapid development of tolerance to the acute deleterious psychomotor effects of CBZ.

Treatment of epilepsy in mentally retarded patients with a slow‐release carbamazine preparation

Pharmacokinetic properties and efficacy of a conventional (C) carbamazepine (CBZ) preparation divided into three daily doses and a slow-release CBZ preparation (SR) divided into two daily doses were evaluated in a randomized, double-blind, cross-over study. The trial started with a 8-week baseline period followed by the two treatment periods each 10 weeks long. At the end of each period, a 24-h blood sample series for determination of serum CBZ and carbamazepine-10,11-epoxide (CBZE) was collected. The occurrence of seizures was monitored day and night during the whole study period by experienced nurses. The mean age of the 20 evaluable patients was 24.9 and the duration of epilepsy 19.2 and carbamazepine treatment 7.0 years. The bioavailability of CBZ from the two preparations was similar. The mean fluctuation of serum CBZ concentration (Cmax-Cmin/Css) was 16% smaller during SR. The mean serum CBZ concentration in the morning samples was significantly (P less than 0.001) higher during SR treatment. The mean total number of seizures was approximately four per week and did not differ between the two treatments, but during the last 2 weeks of the study period the occurrence of seizures was significantly smaller during SR (P = 0.02).

Effect of Serum Separator Tubes on Free and Total Phenytoin and Carbamazepine Serum Concentrations

The effect of serum separator tubes (SSTs) on free and total serum phenytoin and carbamazepine concentrations was determined by comparing standard no-additive tubes with SSTs (Becton Dickinson SST and Terumo Autosep). The influence of time prior to centrifugation, sample volume, and initial drug concentration on the effects were also studied. Results were analyzed using repeated measures two-way analysis of variance with tube type and either time, sample volume, or concentration as main effects. The most significant reductions noted were with Becton Dickinson SSTs in free and total serum phenytoin and total carbamazepine concentrations, where all reductions were less than 10%. The only factor to significantly influence extent of reduction was the effect of time on total serum phenytoin concentration in Becton Dickinson SSTs. Terumo Autosep tubes caused no major reductions in free or total phenytoin or carbamazepine serum concentrations. Autosep tubes should provide accurate measurements of total and free serum phenytoin and carbamazepine concentrations. With Becton Dickinson SSTs, the reductions noted in free and total phenytoin and total carbamazepine concentrations were not large enough to preclude their clinical use. Becton Dickinson SSTs should not be used for determining free or total phenytoin or total carbamazepine concentrations for purposes of research.

Asterixis as a side effect of carbamazepine therapy

A patient developed asterixis 13 weeks after starting a therapy with carbamazepine. Serum concentration of carbamazepine was within the therapeutic levels. Further factors which might have provoked asterixis were an impairment of pulmonary function and the combination with a neuroleptic and lithium. Since the latter risk factors had already been present for a long time, it may be assumed that the addition of carbamazepine triggered the development of asterixis.

Impaired Water Homeostasis following Mixed Carbamazepine and Phenobarbital Overdose

Both carbamazepine and phenobarbital are known to have antidiuretic properties when administered chronically. We describe a case of acute impairment of body water homeostasis following mixed drug overdose with carbamazepine and phenobarbital. Serum carbamazepine concentrations correlated with alternating states of diuresis and antidiuresis. We recommend close monitoring of fluid and electrolyte status in carbamazepine overdose.

Intraindividual Variability of Carbamazepine, Phenobarbital, and Phenytoin Concentrations in Saliva

The intraindividual variability of salivary carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations was studied in six healthy male volunteers. During three consecutive 1-week phases, subjects took one of the antiepileptic drugs (AED) for 5 days. Nine saliva and nine blood samples were collected simultaneously over the last 4 days of each phase. Salivary, unbound serum, and total serum CBZ, PB, and PHT concentrations were determined by fluorescence polarization immunoassay. Individual mean saliva (Cs)/total serum (Ct), unbound serum (Cu)/Ct, and Cs/Cu concentration ratios for CBZ, PB, and PHT were similar to those reported previously. The intraindividual mean (+/- SD) coefficients of variation (%) of the Cs/Ct, Cu/Ct, and Cs/Cu ratios for CBZ were 4.8 +/- 2.2%, 4.4 +/- 1.8%, and 5.0 +/- 1.9%, respectively; for PB they were 5.1 +/- 0.8%, 3.6 +/- 0.9%, and 6.4 +/- 1.0%, respectively; and for PHT they were 7.4 +/- 3.1%, 5.5 +/- 1.2%, and 8.3 +/- 3.2%, respectively. The mean Cs/Ct and Cu/Ct ratios for CBZ and PHT were not significantly different, but they were different for PB (p = 0.01). However, the range of individual coefficients of variation of the Cs/Ct ratio for PB was 4.0-6.2%, which is acceptable for clinical monitoring. We conclude that the intraindividual variability of CBZ, PB, and PHT concentrations in saliva, based upon the saliva/serum concentration ratios of each AED, is not a factor that should dissuade clinicians from using saliva for the therapeutic monitoring of these agents.