Free Carbamazepine Research Articles

Poloxamer®s anchored with TAT enhance blood–brain barrier penetration of carbamazepine for the treatment of epilepsy: an in vivo study

Carbamazepine is a pharmacological medication commonly prescribed to treat epilepsy. Dose adjustments, poor bioavailability, and prolonged side effects present significant challenges associated with its use. Poloxamer micelles have demonstrated exceptional properties as nanocarriers for drug delivery. This research aimed to develop Poloxamer nanomicelles containing carbamazepine and assess their potential to cross the blood–brain barrier.Poloxamer 407 and P-85 micelles, anchored with TAT as a ligand and containing carbamazepine, were prepared. The morphology, entrapment efficiency, drug release, stability, and toxicity of nanomicelles were examined, along with animal studies conducted to evaluate their anticonvulsant effects. The distribution of carbamazepine-Poloxamer in the brain and plasma was assessed.The results indicated the successful formation of spherical nanomicelles with an average size of less than 100 nm, and carbamazepine was effectively incorporated into the micelles. Formulations composed of mixtures of Poloxamer exhibited a high encapsulation efficiency of approximately 92.1% and remained stable for three months. A sustained release of carbamazepine was observed for up to 72 h. The anticonvulsant effect of carbamazepine-loaded nanomicelles in mice was found to be significantly greater than that of those treated with carbamazepine solution, with the effect increasing by approximately tenfold. Compared to free carbamazepine, the carbamazepine-loaded nanomicelles exhibited a 5.5-fold increase in the brain targeting index, with no toxicity observed in mice treated with these nanomicelles. These findings suggest that Poloxamer micelles represent a promising nanoscale, controlled-release delivery system that is free from toxicity and can enhance the penetration of carbamazepine into the brain while improving its anticonvulsant activity.Graphical

Development and Validation of a Free Carbamazepine Assay on an Automated Chemistry Analyzer.

Carbamazepine is an effective drug for treating seizures and trigeminal neuralgia. Therapeutic drug monitoring of free carbamazepine in serum can be useful in situations that drug--protein binding is altered to guide regimen adjustment and to aid in the diagnosis of clinical toxicity. Separation of the nonprotein bound carbamazepine was achieved via ultrafiltration through a molecular weight cut-off filter. A method for free carbamazepine measurement was developed on the automated cobas chemistry analyzers (Roche Diagnostics) by modifying the Carbamazepine Gen 4 assay (Roche Diagnostics). Assay performance characteristics were established including precision, accuracy, reportable range, analytical specificity, and stability. The intra- and inter-assay imprecision was 0%-1.4% and 2.4%-5.1%, respectively. The lower limit of quantitation was 0.3 µg/mL, and the assay was linear up to 10.0 µg/mL. A spike recovery study, using reference standard material, showed recovery was 93.5%--101.3% across the analytical measurement range. Method comparison with a reference laboratory method demonstrated equivalent performance with a slope of 1.01, intercept of 0.09, and correlation coefficient of 0.9948. This assay provides a simple and accurate method for monitoring free carbamazepine with a fast turnaround time.

Matrix-Assisted Cocrystallization (MAC) Simultaneous Production and Formulation of Pharmaceutical Cocrystals by Hot-Melt Extrusion

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals.

Carbamazepine clearance and seizure stability during pregnancy

The aims of this study were to characterize the alterations in total and free carbamazepine (CBZ) and in total and free carbamazepine-epoxide (CBZ-EPO) clearances during pregnancy, to calculate the change in free fractions of CBZ and CBZ-EPO during pregnancy, and to determine whether seizure worsening is associated with a low ratio to nonpregnant baseline concentration of total or free CBZ or CBZ-EPO. Women on CBZ were enrolled before conception or during pregnancy in this prospective, observational study. Concomitant medications and seizure frequency were recorded. Serum total and free CBZ and CBZ-EPO were collected at each visit. Changes in the clearance of all four compounds and free fractions of CBZ and CBZ-EPO were compared with nonpregnant baseline. During pregnancy, the ratios to baseline concentrations of total and free CBZ and CBZ-EPO were compared for months with and without increased seizure frequency. Total and free CBZ and CBZ-EPO clearances were calculated in 15 pregnancies in 12 women. Clearances did not change for any of these compounds during pregnancy. The free fraction of CBZ increased from 0.23 at baseline to a maximum of 0.32 in the third trimester (p=0.008). In the six women on CBZ monotherapy with adequate seizure diaries and blood sampling, seizure worsening did not correspond to a ratio to baseline concentration of less than 0.65 for total or free CBZ or CBZ-EPO. In conclusion, total and free CBZ and CBZ-EPO clearances did not change substantially during pregnancy, and seizure frequency worsening was not associated with decreased concentrations of total or free CBZ; therefore, therapeutic drug monitoring may not be necessary for all women on CBZ during pregnancy. Further studies with larger sample sizes are needed before definitive recommendations can be made. Carbamazepine monotherapy may be a relatively safe and cost effective treatment option for women with focal epilepsy syndromes during pregnancy.

Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs)

PurposeLevetiracetam (LEV) therapeutic range (20–40mg/L) and potential drug interactions were assessed in people with epilepsy (PWE). MethodFifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20–40mg/L – LEV; 25–50μmol/L – total CBZ; 6–13μmol/L – free CBZ; 300–750μmol/L – total VPA; 30–75μmol/L – free VPA; and 40–60μmol/L – LTG. Seizure-freedom was assessed and patients followed for almost two years. Results23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had ‘therapeutic’ LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had ‘therapeutic’ LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy. ConclusionLEV range (20–40mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy.

Effect of volume ratio of ultrafiltrate to sample solution on the analysis of free drug and measurement of free carbamazepine in clinical drug monitoring

Traditional ultrafiltration (UF) usually has a large volume ratio of ultrafiltrate to sample solution, and this ratio cannot be well controlled. It can break the balance of protein-binding equilibrium and exert an influence on the analysis of free drug. In the present study, we evaluated the influence of volume ratio of ultrafiltrate to sample solution on the analysis of free drug in human plasma. We used carbamazepine as a model drug and studied the effect of different centrifugation times on ultrafitrate volume and the related effects on unbound carbamazepine measurement. Moreover, we compared the hollow fiber centrifugal ultrafiltration (HFCF-UF) with traditional UF. Our results showed that the ultrafiltrate volume was changed from 40 to 400μL with the increase of centrifugation time for the traditional UF, and the related changes in unbound concentration were significant. The rate of protein binding (BP) was changed from 40% to 70%. In contrast, a tiny and invariant ultrafiltrate yield (40μL) was obtained using the HFCF-UF method, and the BP rate was around 72%. In addition, with the HFCF-UF method, the volume ratio of ultrafiltrate to sample solution could be also well controlled by the inner diameters of both the glass tube and hollow fiber. The HFCF-UF method was a more accurate plasma pretreatment procedure, by which the in vivo balance of protein-binding equilibrium was hardly broken. Therefore, this method was successfully employed to quantify the free fraction of carbamazepine in clinical samples.

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

Flow injection on-line oxidizing fluorometry coupled to dialysis sampling for the study of carbamazepine–protein binding

The mechanism of binding of carbamazepine (CBZ) with bovine serum albumin (BSA) has been investigated in vitro based on a new flow injection fluorometry coupled to the technique of dialysis sampling. The CBZ and BSA were mixed in different molar ratios in 0.050 mol L −1 phosphate buffer (containing 0.9% NaCl), pH 7.4, and incubated at 37 ± 0.5 °C in a water bath. The dialysis sampler was utilized to sample free CBZ from mixed solution with a relative dialytic efficiency of 7.6%. Then the CBZ in dialysis solution was injected into carrier and on-line oxidized by lead dioxide solid-phase reactor into fluorescent product with a maximum excitation wavelength of 355 nm and a maximum emission wavelength of 478 nm. The fluorescence intensity measured was linear proportional with the concentration of free CBZ in mixed solution over the range of 1 × 10 −5 to 2 × 10 −4 mol L −1 with the detection limit of 6 × 10 −6 mol L −1. According to the fluorescence measurement results from mixed solution, the association constant ( K) estimated for CBZ–BSA binding and the number of the binding site ( n) with Scatchard analysis were 1.08 × 10 4 L mol −1 and 0.94, respectively. Stern–Volmer plots indicated the presence of dynamic component in the quenching mechanism. The acting force was suggested to be mainly hydrophobic and the distance between the acceptor and donor was 3.12 nm. The estimated binding parameters agreed well with literature values.

Cortical excitability during prolonged antiepileptic drug treatment and drug withdrawal

Objective Previous reports characterized the effects of administration of single oral doses of antiepileptic drugs (AED) on cortical excitability. However, AED effects on cortical excitability, and their relationship to plasma blood levels, during chronic drug administration at therapeutic doses are not known. The objective of the study was to determine whether plasma blood levels during chronic administration at therapeutic doses would accurately predict changes in corticomotor excitability. Methods We used transcranial magnetic stimulation (TMS) to measure cortical excitability during 5 weeks administration of carbamazepine (CBZ) and lamotrigine (LTG), and subsequent AED withdrawal in 20 healthy volunteers. Data were analyzed using ANOVA RM and regression analysis. Results Resting motor thresholds (r-MT) increased with increasing total and free CBZ and LTG levels during drug administration, but not drug withdrawal. After acute AED withdrawal, r-MT elevation persisted in most individuals with CBZ despite undetectable plasma levels, compared to a rapid normalization with LTG. In contrast, acute drug withdrawal resulted in a transient decrease in r-MT in 3/10 individuals with CBZ and 2/10 with LTG. Conclusions Plasma levels provide information on motor cortical function during active treatment phases but not during AED withdrawal. Significance The transient decrease in r-MT associated with acute AED withdrawal could represent a physiological substrate contributing to AED withdrawal seizures.

Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients

Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential effects of zonisamide on carbamazepine pharmacokinetics (PK) have not been well characterized, with contradictory literature reports. Hence, an in vitro study was designed to evaluate the cytochrome P450 inhibition spectrum of zonisamide using human liver microsomes. Further, an in vivo steady-state study was performed to measure the effect of zonisamide on carbamazepine PK in epileptic patients, and monitor zonisamide PK. In vitro human liver microsomes were incubated with zonisamide (200, 600 or 1000 μM) in the presence of appropriate probe substrates to assess selected cytochrome P450 activities. In vivo, the effect of zonisamide, up to 400 mg/day, on the steady-state PK of carbamazepine and carbamazepine-epoxide (CBZ-E) was studied in 18 epileptic patients. In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1. The estimated K i for zonisamide inhibition of CYP3A4 was 1076 μM, 12 times higher than typical unbound therapeutic serum zonisamide concentrations. In vivo, no statistically significant differences were observed for mean C max, T max, and AUC 0–12 of total and free carbamazepine and CBZ-E measured before and after zonisamide administration (300–400 mg/day for 14 days). However, CBZ-E renal clearance was significantly ( p < 0.05) reduced by zonisamide. The observed mean zonisamide t 1/2 (36.3 h), relative to approximately 65 h reported in subjects on zonisamide monotherapy, reflects known CYP3A4 induction by carbamazepine. Based on the lack of clinically relevant in vitro and in vivo effects, adjustment of carbamazepine dosing should not be required with concomitant zonisamide administration.

Effect of heating human sera at a temperature necessary to deactivate human immunodeficiency virus on measurement of free phenytoin, free valproic acid, and free carbamazepine concentrations.

Minimizing the risk for infection to laboratory staff from a contaminated blood sample is a major safety goal in the clinical laboratory. One dangerous pathogen, the human immunodeficiency virus (HIV), can be deactivated by heating sera at 56 degrees C for 30 minutes. The authors previously reported that if serum was subjected to those conditions, the concentrations of the nine most commonly monitored drugs were not altered, whereas phenytoin and carbamazepine concentrations were reduced slightly. Monitoring free phenytoin, free valproic acid, and free carbamazepine concentrations is strongly recommended for patients with uremia, liver disease, and hypoalbuminemia. Because drug protein binding can be affected by temperature, the authors investigated the effect on free drug concentrations of sera heated to levels necessary for deactivation of the HIV virus. They measured total and free drug concentrations in serum pools prepared from patients receiving phenytoin, valproic acid, and carbamazepine. Serum pools were heated at 56 degrees C for 30 minutes and then brought to room temperature. The total and free drug concentrations were measured immediately after heating and then at 20- and 45-minute intervals. The concentrations of free phenytoin and free valproic acid were significantly higher after heat treatment. However, after equilibration of sera at room temperature for 20 minutes, the free concentrations of phenytoin were comparable to preheating values, although total phenytoin concentrations (Serum Separator Tubes) were reduced slightly. In contrast, free valproic acid concentrations did not return to the original levels even after 45 minutes. Free carbamazepine concentrations did not change even immediately after heating. However, total carbamazepine concentrations were reduced slightly when sera were heated in serum separator tubes (SST Tubes).

Determination of Free Serum Carbamazepine by Protein Precipitation with Sulphosalicylic Acid

The aim of this study was to demonstrate the good correlation between free serum concentrations of carbamazepine obtained by ultrafiltration and protein precipitation with sulphosalicylic acid. Serum samples from 37 outpatients chronically treated with carbamazepine were analysed. Free carbamazepine was determined by fluorescent polarization immunoanalysis. The mean free serum concentrations obtained by each technique were compared using the t-test for paired samples. The mean free serum concentrations of carbamazepine obtained by ultrafiltration and protein precipitation were 1.61 and 1.75 mgL−1, respectively. No significant difference was found between the two methods. There was good correlation (r = 0.97; 95% confidence interval = 0.95-0.99) between the free serum concentrations obtained by each separation method. Protein precipitation with sulphosalicylic acid could be used instead of ultrafiltration to obtain free serum carbamazepine. It gives similar results and is simpler, quicker and cheaper.

Six mutagenicity assays in exposure biomonitoring of patients receiving carbamazepine for epilepsy or trigeminal neuralgia

The mutagenic potential of carbamazepine (CBZ) therapy has been studied in 37 patients undergoing long-term treatment with this drug. Of the total group, 23 patients suffered from epilepsy and 14 from trigeminal neuralgia. Thirty-one healty subjects served as controls. Six mutagenicity assays with different end-points were performed. The possible cytogenetic alterations were evaluated by analyzing sister-chromatid exchange frequencies (SCE), chromosome aberrations (CA), micronuclei (MN), proliferation indices (PRI), and mitotic indices. The Salmonella assay with and without microsomal activation served to measure urinary mutagenicity. The results show that CBZ leads to an increase in SCE ( p < 0.01) and PRI ( p < 0.05) but had no effect on the other cytogenetic parameters. CBZ was negative in the urine mutagenicity test. Plasma levels of total CBZ, free CBZ and CBZ-10, 11-epoxide did not correlate with the cytogenetic alterations. Even though folic acid and γ-glutamyltranspeptidase were significantly different in patients and controls, there was no significant association between these values and SCE or PRI. Patients with epilepsy and those with trigeminal neuralgia did not differ with respect to the end-points analyzed.

Carbamazepine-Salicylate Interaction in Normal and Uremic Sera

Displacement of phenytoin and valproic acid by salicylate have been described. We studied carbamazepine-salicylate interactions in normal and uremic sera, which have not been studied. Salicylate caused significant displacement of carbamazepine from protein binding, leading to higher concentrations of free carbamazepine. The concentrations of free carbamazepine were always significantly higher in uremic sera than in normal sera. However, when uremic sera were supplemented with both carbamazepine and salicylate, we observed a much lower displacement of carbamazepine and only a slight increase in free carbamazepine concentration. Treatment of uremic sera with activated charcoal corrected the binding deficiency for carbamazepine. Known uremic compounds like hippuric acid and indoxyl sulphate can only partly explain the observed displacement of carbamazepine in uremic sera. We conclude that salicylate displaces carbamazepine from protein binding in normal sera, but this interaction is significantly reduced in uremic sera.

Improved therapeutic monitoring of drug interactions in epileptic children using carbamazepine polytherapy.

Drug interactions in epileptic children with carbamazepine (CBZ) polytherapy were investigated by analysis of total and free CBZ and its metabolites simultaneously. Heteroinduction effects of CBZ metabolism by other antiepileptic drugs (AEDs), including phenytoin (PHT), phenobarbital (PB), or primidone (PRM), were clearly demonstrated. Serum CBZ level/dose ratios in patients taking CBZ plus other AEDs were decreased while CBZ-10,11-epoxide (CBZ-E) and trans-10,11-dihydroxy-10,11-dihydro-CBZ (CBZ-H) concentrations were significantly increased compared to patients with CBZ alone. Concentration ratios of CBZ-H/CBZ and CBZ-E/CBZ were also significantly higher in patients taking CBZ plus other AEDs. Interactions between CBZ and valproic acid (VPA) involved both protein binding displacement and metabolic inhibition. Patients taking CBZ plus VPA showed significantly increased free fractions of CBZ and CBZ-E and substantially increased serum CBZ-E concentrations and CBZ-E level/dose ratios, while CBZ-H/CBZ-E concentration ratios were decreased compared with patients on CBZ alone. Since this approach investigates the in vivo relationship between substrates and products of the enzymes involved in CBZ biotransformation (the ratios between CBZ and its metabolites), detailed information about the activities of the enzymes may be obtained. This approach appears to be a practical way to improve the monitoring of CBZ metabolism influenced by various physiological or pathological conditions and achieve a better understanding of the drug interactions under different drug regimens (coadministered inhibitor or inducer). This principle may also be adopted for other drugs with similar metabolic characteristics.

Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

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.

Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients

Twenty-four epileptic patients (16 females, 8 males; aged 13–62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300–1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10,11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P < 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25–69 mg/l), as CBZ-E concentrations correlated significantly with total ( r = 0.5, P < 0.05, 95% CI 0 to + 0.08) and free ( r = 0.7, P < 0.001, 95% CI + 0.09 to + 0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.

The Influence of Electroencephalographic Focus Laterality on Efficacy of Carbamazepine in Complex Partial and Secondarily Generalized Tonic‐Clonic Seizures

Forty-five outpatients with chronic epilepsy with complex partial seizures (CPS) alone or associated with secondarily generalized tonic-clonic seizures (SGTCS) were treated with carbamazepine (CBZ) monotherapy. All patients had only a unilateral scalp electroencephalographic (EEG) focus. Left- (n = 29) and right- (n = 16) sided foci patients were comparable for age, sex, duration, and etiology of epilepsy as well as total and free CBZ serum levels. CBZ significantly improved CPS irrespective of the side of the EEG focus, whereas SGTCS were controlled for greater than 1 year in 15 of 19 patients with left focus and in three of 11 patients with right focus. When patients with poorly controlled seizures discontinued CBZ and changed to other therapies, they achieved a significant reduction in number of SGTCS, whereas the number of CPS was unchanged. The side of EEG focus seemed to be relevant to the control of SGTCS by CBZ. Interhemispheric neurotransmitter asymmetries may be involved in the EEG focus side-dependent CBZ response.

Carbamazepine Metabolism in Humans

Free and total carbamazepine (CBZ) and carbamazepine-epoxide (CBZ-EP) plasma levels were obtained on 113 patients with epilepsy (18-61 years old) controlled on either monotherapy or coadministration with either phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), or all three. A subset of patients were administered tetradeuterium labeled CBZ to evaluate the effects of autoinduction and coadministration of VPA on the kinetics of CBZ and its metabolite CBZ-EP. Polytherapy had variable effect on free and total CBZ plasma levels compared to monotherapy. Coadministered PHT (co-PHT), or all three anticonvulsants together (PHT, PB, and VPA: co-AEDs) decreased free and total CBZ plasma levels. No change was noted for coadministered VPA (co-VPA). Compared to monotherapy the free and total CBZ-EP levels increased with co-VPA, less with coadministered PB (co-PB), and no change with co-PHT or co-AEDs. Protein binding of CBZ and CBZ-EP was not affected by any antiepileptic drugs studied. The free and total CBZ-EP/CBZ ratio was tripled with co-VPA or co-AED's, and doubled with co-PHT or co-PB. Isotope labeling did not demonstrate any differences in half-life (t1/2), plasma clearance (Cl), or volume of distribution (Vd). Compared to naive controls, monotherapy and co-VPA decreased CBZ t1/2 by 50%, and more than doubled the CBZ Cl without a significant change in the Vd. Autoinduction is one explanation for these changes with chronic CBZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)