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At least 19 recordsLinked to original sources
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↗
PubMed1976

Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy.

Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 +/- 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 +/- 2.5 mug/ml and 1.10 +/- 0.42 mug/ml, respectively. A singificant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p less than 0.001), but marked interindividual variation existed in the ratio of carbamazepine to carbamazepine to epoxide. Based on simultaneous measurements in plasma and cerebrospinal fluid, the unbound fraction of carbamazepine in plasma was of the order of 20% as compared to 45% for the epoxide. Thirteen ambulant patients suffering from partial epilepsy with complex symptomatology, who were already being treated with phenytoin in optimal doses (plasma level 14-20 mug/ml) were also given carbamazepine. At plasma levels of the latter of about 5 mug/ml there was no further reduction in the frequency of partial or generalized epileptic seizures. In five patients the dose was increased to produce plasma concentrations of 7 - 8 mug/ml. There was still no improvement and side-effects were seen in three patients.

Carbamazepine↗
PubMed1992

An immunodominant haptenic epitope of carbamazepine detected in serum from patients given long-term treatment with carbamazepine without allergic reaction.

An anticarbamazepine antibody was detected in the serum of a patient with severe carbamazepine-induced serum sickness. We found that the patient's T cells and IgG antibody recognized an epitope which appeared in subjects showing an allergic reaction, as well as that in subjects who showed no allergic reaction, after long-term carbamazepine therapy. These results show that an anti-carbamazepine immune response does not occur in the majority of subjects who undergo long-term carbamazepine therapy without developing allergic symptoms, although the immunodominant haptenic epitope of carbamazepine is present in their sera.

Carbamazepine↗
PubMed1976

Serum concentration of carbamazepine: comparison of Herrmann's spectrophotometric method and a new GLC method for the determination of carbamazepine.

A specific direct gas chromatographic method to determine carbamazepine and, semiquantitatively, 10,11-epoxy carbamazepine in serum is described. The average recovery of carbamazepine is 98%, and the error on duplicate determination is +/- 4%. The method is compared with Herrmann's classic spectrophotometric method. In material of 103 patients the mean serum concentration of carbamazepine was 25.5 +/- 12.8 mumoles/1 with GLC and 23.0 +/- 12.6 mumoles/1 with spectrophotometry. The difference was highly significant. The blood sample volume is one-tenth of that needed in spectrophotometry.

Carbamazepine↗
PubMed1978

Kinetics of carbamazepine and carbamazepine-epoxide, determined by use of plasma and saliva.

The concentration-time curves of carbamazepine (CBZ) and its metabolite (carbamazepine-10,11-epoxide; CBZ-epoxide) were determined in patients undergoing long-term antiepileptic drug treatment with the use of plasma and saliva data. Plasma and saliva samples were assayed concurrently for each patient by liquid chromatography. There was excellent linear correlation between CBZ levels in saliva and plasma (r = 0.991, p less than 0.001) over a large concentration range. The saliva/plasma ratio for CBZ concentration was 0.26 +/- 0.01 (SD). Since CBZ binding to plasma proteins is in the order of 76%, saliva CBZ concentration seems to reflect the unbound fraction of the drug in plasma. CBZ-epoxide has not been detected in saliva. The pharmacokinetic parameters of CBZ-epoxide were determined in 6 patients. The pharmacokinetic parameters of CBZ obtained from saliva concentrations were in excellent agreement with those obtained from plasma concentrations. Thus, CBZ determination in saliva is convenient for controlling blood levels in patients as well as for studying pharmacokinetics. The half-life, the relative body clearance of CBZ, and the metabolite concentration during steady-state, expressed as percent the parent compound, appear to be significantly different in patients on single and combined drug therapy.

Adolescent↗
PubMed1978

Brain concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients.

Carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-Epoxide) in the temporal lobe were measured in five epileptic patients undergoing unilateral temporal lobectomy. The patients had been under CBZ treatment from 6 months to 6 years and all were in steady state at the time of operation. The brain tissue concentration of CBZ in all patients was higher than the plasma concentration; the brain/plasma ratio ranged from 1.4--1.6. Brain/plasma ratios of CBZ-Epoxide ranged from 0.6--1.5. The ratio for CBZ was similar in patients treated with CBZ alone or in combination with other anticonvulsants, but for the CBZ-Epoxide a higher ratio was found in patients on combined treatment. The results may mean that other antiepileptic drugs, too, can influence the brain concentration of an active metabolite, which could have a bearing on the enhanced therapeutic effect often seen on combining CBZ treatment with other antiepileptic drugs.

Adolescent↗
PubMed1977

Carbamazepine and carbamazepine-10, 11-epoxide concentrations in human brain.

1 Carbamazepine (CBZ) brain and plasma concentrations were measured in twenty-one patients undergoing brain surgery for tumour removal. The drug was administered prophylactically at doses ranging from 6.9 to 14.8 mg/kg for 4-5 days before the intervention. 2 In seventeen cases where sample were collected 10-14 h after dosing, CBZ brain levels ranged from 2.2-14.5 microgram/g. A significant linear relationship (p less than 0.01) was observed between brain and plasma concentrations with a brain/plasma ratio of 1.1 +/- 0.1. 3 Carbamazepine 10,11-epoxide (CBZ-Epox), present in all samples, could be quantified in three brain specimens. Its brain concentrations ranged from 1.5-2.7 microgram/g with a brain/plasma ratio of 1.1-1.2. 4 Parieto-occipital areas tended to show higher CBZ concentrations while lower values were found in temporal regions. Very low CBZ levels were found in two gliomas while in meningiomas CBZ levels were similar to those observed in normal tissue. 5 The data, showing a linear relationship between brain and plasma concentrations of both CBZ and its epoxide, give additional significance to the plasma level monitoring of antiepileptic drugs.

Adult↗
PubMed1978

Carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in brain tissue of epileptic children.

Carbamazepine (CBZ), carbamazepine-10,11-epoxide (CBZ-epoxide) and phenytoin (DPH) were measured in brain tissue in two epileptic children undergoing temporal lobectomy. The patients had been treated with the anticonvulsants in question for 2 years. The CBZ concentration in brain tissue was higher or equal to the plasma concentration. Brain/plasma ratio for CBZ was 1.0 and 1.4, respectively (grey substance). Brain/plasma ratio of CBZ-epoxide was 1.0. Concomitant treatment with DPH increased the percentage of CBZ-epoxide relative to CBZ in both brain and plasma. In white brain substance the concentration of CBZ, CBZ-epoxide and DPH was higher or equal to the corresponding concentration in grey substance. No major age-related differences in the distribution of anti-epileptic drugs between brain and plasma in these two children compared to adult epileptic patients were noted. A new quantitative thin-layer chromatographic method for the determination of DPH and phenobarbital (PB) in brain tissue and plasma is described.

Brain↗
PubMedDate not supplied

Clinical pharmacokinetics of carbamazepine.

Carbamazepine seems to as effect as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia. After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics. Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10,11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine doses has been identified as metabolites in the urine. The quantitatively most important metabolites is the trans-10,11-dihydro-10,11-diol. The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults. A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects. Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10microgram/ml (20 to 40mumol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

Carbamazepine↗
PubMed1992

Carbamazepine kinetics and adverse effects during and after ethanol exposure in alcoholics and in healthy volunteers.

The influence of ethanol on the single-dose kinetics of carbamazepine (400 mg syrup) was assessed in 7 alcoholics after a debauche (mean daily consumption 240 g ethanol) and after 9 days of controlled abstinence, and in 8 healthy volunteers after intake of the drug with and without a single dose of ethanol (25 g). Twelve h after the first test dose of carbamazepine the alcoholics were treated with the drug for 4 days (200 mg tablet b.d.). Carbamazepine was then withheld until a single test dose was given on day 9. Serum levels of carbamazepine and its 10,11-epoxide metabolite were measured by liquid chromatography. Carbamazepine absorption appeared to be delayed in alcoholics, both after debauche and withdrawal, but its bioavailability did not seem to be reduced. Carbamazepine levels were higher and those of its metabolite lower in alcoholics after a debauche than after 9 days of controlled abstinence, but neither was changed in healthy volunteers after the ingestion of carbamazepine together with a single dose of ethanol. The difference may have been due to inhibition of carbamazepine metabolism by ethanol at the high levels attained in alcoholics but not in volunteers. However, it could also be an expression of the unmasking of enzyme induction after ethanol withdrawal. None of the alcoholics had any withdrawal seizures. Despite similar carbamazepine levels, side effects occurred in all volunteers but in none of the alcoholics, indicating that long-term ethanol exposure may promote central nervous adaptation to the acute untoward effects of carbamazepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.

BACKGROUND: Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin. METHODS: We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred. RESULTS: For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001). CONCLUSIONS: Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects.

Adolescent↗
PubMed1979

The epoxide of carbamazepine.

Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide have been measured by high pressure liquid chromatography in 101 epileptic children and adults taking the drug. There was either no statistically significant correlation, or only a very poor correlation, between drug dose and steady-state plasma levels of a) carbamazepine, b) its epoxide, and c) the sum of drug and epoxide. Plasma concentrations of carbamazepine correlated with those of it epoxide. Plasma carbamazepine levels were lower in patients taking phenytoin with carbamazepine than in patients taking carbamazepine alone. Plasma carbamazepine-10,11-epoxide levels were not definitely altered when carbamazepine and phenytoin were used together. This finding is consistent with the hypothesis that phenytoin enhances the metabolism of carbamazepine to a metabolite other than its epoxide.

Adolescent↗
PubMed1979

Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy.

The kinetics of carbamazepine using 15N-carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N-carbamazepine plasma half-lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half-lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady-state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine-trans-diol, 5.2% to 8.8% as 9-hydroxymethyl-10-carbamoyl acridane, 1% to 1.4% as 10,-11-carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide-diol pathway which is induced during long-term treatment. Concomitant therapy with primidone, phenytoin, phenobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

Adult↗