10,11-Dihydro-10,11-dihydroxy-5H-dibenz[b,f]azepine-5-carboxamide, a metabolite of carbamazepine isolated from human and rat urine

Baker, Kenneth M.; Csetényi, J.; Frigerio, A.; Morselli, P. L.; Parravicini, F.; Pifferi, G.

doi:10.1021/jm00264a028

Cited by 28 publications

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“…Oxcarbazepine (172 g, 0.826 mol) was suspended in a mixture of water (0.4 L) and ethanol (0.7 L), sodium borohydride (20 g, 0.526 mol) was added in portions over 10 min without cooling, and stirring continued at 45 °C for 1 h. Acetone (150 mL) was added cautiously, and the reaction mixture was evaporated down to a small volume. Addition of water precipitated the product (157.8 g, 91%): mp 185−188 °C (lit . mp 188−192 °C); 1 H NMR (CDCl 3 ) δ 7.7−7.1 (m, 8H, Ar−H), 5.3, 4.7 (2 × br s, 1H, C 10 −H), 4.9 (br s, 2H, NH 2 ), 3.7, 2.7 (2 × br s, 1H, −OH), 3.5 (m, 1H, C 11 −H), 3.0 (m, 1H, J = 15 Hz, C 11 −H).…”

Section: Methodsmentioning

confidence: 99%

Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

et al. 1999

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A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

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Section: Methodsmentioning

confidence: 99%

Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

et al. 1999

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“…Phenobarbitone (PHB) induces the arene oxide pathway by which xenobiotics can be hy-droxylated through epoxide intermediates. There is evidence that several other antiepileptic drugs, such as phenytoin (DPH) and carbamazepine (CBZ), are metabolized in this pathway (Baker et al, 1973;Horning et al, 1975). Therefore, the production and half-life of epoxide intermediates may depend on which specific combination of drugs is used.…”

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confidence: 99%

Teratogenicity of Antiepileptic Drug Combinations with Special Emphasis on Epoxidation (of Carbamazepine)

1984

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A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.

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“…The synthesis of the tetradeuterated CB-cis-diol is more labour intensive than the synthesis of the unlabelled diol. Unlabelled CB-10,ll-cis-diol can be synthesized easily, according to Baker et al, 26 with osmium tetroxide. Tomson et al report that the TMS derivatives had to be measured within 1 h. Apparently, these derivatives are not very stable in hexane after evaporation of the silylating reagent.…”

Section: Discussionmentioning

confidence: 99%

Gas chromatographic/mass spectrometric assays for oxcarbazepine and its main metabolites, 10-hydroxy-carbazepine and carbazepine-10,11-trans-diol

Unruh

Paar

1986

Biol. Mass Spectrom.

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Oxcarbazepine (OCB) cannot be measured undecomposed by gas chromatography, not even when injected into a cooled, inert fused-silica capillary column. The bis-trimethylsilyl derivatives of the enol of OCB and of its main metabolite, 10-hydroxy-carbazepine (10-OH-CB), and the tris-trimethylsilyl derivative of carbazepine-10,11-trans-diol (CB-trans-diol) can be obtained easily at room temperature and are well suited for gas chromatographic and gas chromatographic/mass spectrometric analysis. Thermal decomposition to the substituted iminostilbene derivatives occurs only to the extent of a few per cent under the conditions described. Two gas chromatographic/mass spectrometric assays have been developed: one for the simultaneous quantification of OCB and 10-OH-CB, the other for CB-trans-diol. Both assays use carbazepine-10,11-cis-diol as the internal standard. Using 0.5 ml of plasma, limits of detection of 0.1, 0.1 and 1 ng/ml were obtained for OCB, 10-OH-CB and CB-trans-diol, respectively. CB-trans-diol is also the main metabolite of carbamazepine in patients under maintenance therapy. The kinetics of 15N-labelled CB-trans-diol derived from a single dose of (15N)carbamazepine has been measured in plasma and urine of patients and volunteers receiving (15N)carbamazepine in several studies.

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10,11-Dihydro-10,11-dihydroxy-5H-dibenz[b,f]azepine-5-carboxamide, a metabolite of carbamazepine isolated from human and rat urine

Cited by 28 publications

References 0 publications

Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

Teratogenicity of Antiepileptic Drug Combinations with Special Emphasis on Epoxidation (of Carbamazepine)

Gas chromatographic/mass spectrometric assays for oxcarbazepine and its main metabolites, 10-hydroxy-carbazepine and carbazepine-10,11-trans-diol

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