 Chemical Structure.png)
Carbamazepine (formerly also known as CBZ, NSC-169864, Carbatrol; Tegretol, Epitol), an approved anticonvulsant drug, is a potent sodium channel blocker with IC50 of 131 μM in rat brain synaptosomes. Carbamazepine is a medication used primarily in the treatment of epilepsy and neuropathic pain. For seizures it works as well as phenytoin and valproate. It is not effective for absence seizures or myoclonic seizures. It may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder.
Physicochemical Properties
| Molecular Formula | C15H12N2O |
| Molecular Weight | 236.27 |
| Exact Mass | 236.094 |
| CAS # | 298-46-4 |
| Related CAS # | Carbamazepine-d10;132183-78-9;Carbamazepine-d2;1189902-21-3;Carbamazepine-d8;1538624-35-9;Carbamazepine-(Ph)d8 |
| PubChem CID | 2554 |
| Appearance | White to off-white solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 411.0±48.0 °C at 760 mmHg |
| Melting Point | 189-192 °C |
| Flash Point | 202.4±29.6 °C |
| Vapour Pressure | 0.0±1.0 mmHg at 25°C |
| Index of Refraction | 1.670 |
| LogP | 2.67 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 1 |
| Rotatable Bond Count | 0 |
| Heavy Atom Count | 18 |
| Complexity | 326 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | RYLOOVOCHDAWIL-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C15H12N2O/c16-15(18)12-9-10-5-1-3-7-13(10)17-14-8-4-2-6-11(12)14/h1-9,17H,(H2,16,18) |
| Chemical Name | benzo[b][1]benzazepine-11-carboxamideInChi Key: RYLOOVOCHDAWIL-UHFFFAOYSA-N |
| Synonyms | NSC 169864; Carbamazepine, NSC 69864; NSC-169864;Tegretol, Epitol |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro |
|
||
| ln Vivo |
|
||
| Animal Protocol |
|
||
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL. The Tmax was reduced to 5.9 ± 1.8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg. **Effect of food on absorption** A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption. After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces. Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug. The volume of distribution of carbamazepine was found to be 1.0 L/kg in one pharmacokinetic study. Another study indicates that the volume of distribution of carbamazepine ranges between 0.7 to 1.4 L/kg.. Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue. Carbamazepine crosses variably through the blood-brain barrier. In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min after one dose of carbamazepine and 80 ± 30 mL/min after several doses. Absorption: Slow and variable, but almost completely absorbed from gastrointestinal tract. Patients in whom carbamazepine monotherapy is discontinued for preoperative EEG/video monitoring often display toxicity if their previous maintenance dosage is resumed, even after a few days without carbamazepine. To determine whether this is due to rapid reversibility of autoinduction of carbamazepine metabolism, single-dose studies of carbamazepine pharmacokinetics were performed before and after discontinuation for monitoring in 6 adults receiving carbamazepine monotherapy. The carbamazepine-free period was 5.7 + or - 1.1 days (mean + or - SD). The pharmacokinetic parameters of carbamazepine before and after discontinuation were volume of distribution 1.28 + or - 0.29 versus 1.22 + or - 0.331/kg, elimination half-life (tl/2) 13.7 + or - 1.67 versus 22.2 + or - 2.36 hr (p < 0.001), and clearance 1.54 + or - 0.39 versus 0.92 + or - 0.32 L/kg/day (p = 0.012). Assuming that deinduction is a first-order process, a deinduction tl/2 of 3.84 days was obtained by log linear regression analysis. We showed that after carbamazepine discontinuation half of the enzymatic autoinduction is already lost after 3.84 days, indicating very rapid deinduction. Our results also provide the necessary information to predict clearance and appropriate dosage reduction for carbamazepine at time of reintroduction. This study was designed to evaluate the usefulness of carbamazepine as a probe in screening for host factor influences on human drug metabolism. Nine healthy nonsmoking volunteers ingested a single oral dose of carbamazepine in doses ranging from 400 to 500 milligrams. Fluorescence polarization immunoassay measurements of carbamazepine concentrations in plasma and plasma ultrafiltrates from 0 to 48 hours after dosing were used to calculate clearance, volume of distribution, and clearance of plasma unbound drug. Blood samples collected 48 hours after dosing gave single sample estimates of carbamazepine clearance which were closest to multiple sample values for clearance. This was also the case for plasma total carbamazepine and plasma unbound carbamazepine. In calculating all single sample estimates of clearance, a value of 1.1 L/kg was used for V and a value of 4.3 L/kg was used to calculate the single sample estimates of clearance of plasma unbound drug. The mean prediction error was less than 5 percent errant for clearance and less than 1 percent errant for clearance of plasma unbound drug when the parameters were calculated from 48 hour concentrations of plasma total carbamazepine or plasma unbound carbamazepine, respectively. ... A fatal overdose of carbamazepine with both timely antemortem and postmortem carbamazepine concentrations /was reported/. Carbamazepine concentrations were 47.7 ug/mL 2 hr antemortem and 53 ug/mL at 9 hr postmortem. The slight rise in drug concentration may reflect continued absorption of the drug in the last 2 hr before death. Postmortem carbamazepine concentrations drawn from a peripheral vessel in this patient appeared to reflect drug concentrations at the time of death. For more Absorption, Distribution and Excretion (Complete) data for CARBAMAZEPINE (15 total), please visit the HSDB record page. Metabolism / Metabolites Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine. The pharmacokinetics of a single oral dose of carbamazepine-10,11-epoxide, (100 mg) were compared in 10 patients on chronic monotherapy with lamotrigine, (200-300 mg/day) and in 10 drug-free healthy control subjects. Carbamazepine-10,11-epoxide pharmacokinetic parameters in lamotridge-treated patients were found to be similar to those observed in controls (half-life: 7.2 + or - 1.6 vs 6.1 + or - 0.9 hr; apparent oral clearance: 110.8 + or - 53.1 vs 120.5 + or - 29.9 ml/h/kg; apparent volume of distribution: 1.08 + or 0.37 vs 1.04 + or - 0.25 l/kg respectively; means + or - s.d.). These data indicate that, contrary to previous suggestions, lamotridge has no effect on the metabolic disposition of carbamazepine-10,11-epoxide. Placental transfer and metabolism of carbamazepine was studied in a dual recirculating placental cotyledon perfusion system and was also evaluated in 16 pairs of maternal venous and cord blood samples. ... Carbamazepine added into the maternal circulation crosses the placenta in the beginning quicker than antipyrine which is in agreement with the different lipid solubilities of these compounds. Because the transfer rates of antipyrine and carbamazepine were about the same, the mechanism of transfer of carbamazepine is probably similar to that of antipyrine (passive diffusion). No metabolites of carbamazepine could be detected in the perfusate by high-performance liquid chromatography or gas chromatography/mass spectrometry. With the improved HPLC methodology for carbamazepine metabolites, six metabolites were detected in clinical samples, including 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ), which has been described earlier in only 1 uremic patient. Relative levels of metabolites showed significant individual differences. Carbamazepine crosses perfused placenta rapidly, but this does not contribute to carbamazepine metabolites detected in maternal and fetal circulation. The aim of this work was to study the transport across the blood-brain barrier, blood and liver distribution kinetics, metabolic interaction and local liver metabolism of carbamazepine in the rat, using microdialysis with the internal standard technique as in vivo calibration method. Carbamazepine and its major metabolite, carbamazepine-10,11-epoxide, are homogeneously distributed to hippocampus and cerebellum. The ratios of the areas under the concentration-time curve for both brain regions to blood areas under the concentration-time curve were not different from unity for carbamazepine; they were 0.46 + or - 0.08 (hippocampus) and 0.45 + or - 0.05 (cerebellum) for carbamazepine-10,11-epoxide. In addition, the disposition of carbamazepine and carbamazepine-10,11-epoxide in blood and liver, after a single dose of carbamazepine, was studied in control animals and in rats after pretreatment with clomipramine. A 2-fold increase in the blood areas under concentration curve of carbamazepine and a decrease to 33% of the blood areas under concentration curve of carbamazepine-10,11-epoxide in the pretreated group demonstrate the metabolic inhibition of carbamazepine-10,11-epoxide formation by clomipramine. The ratios of the areas under concentration curve carbamazepine-10,11-epoxide to the areas under the concentration curve carbamazepine, as a measure of carbamazepine-10,11-epoxide formation, were not different for blood and liver within the control and the clomipramine-pretreated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, carbamazepine was administered locally in the extracellular fluid of the liver via the microdialysis probe. The liver metabolic ratio, expressed as the ratio of the formed carbamazepine-10,11-epoxide concentration to the carbamazepine concentration administered, ranged from 18.2 + or - 1.2% to 19.6 + or - 1.6%. Carbamazepine has known human metabolites that include 9-Hydroxycarbamazepine, Carbamazepine 10,11-epoxide, 2-Hydroxycarbamazepine, and 3-Hydroxycarbamazepine. Hepatic. CYP3A4 is the primary isoform responsible for the formation of carbamazepine-10,11-epoxide. This metabolite is active and shown to be equipotent to carbamazepine as an anticonvulsant. Carbamazepine is more rapidly metabolized to the aforementioned metabolite in younger patients than in adults. It also undergoes glucuronidation via UGT2B7, however this finding has been disputed. Route of Elimination: 72% of the dose is in the urine while 28% is in the feces. Hydroxylated and conjugated metabolites are largely what was recovered in the urine. 3% of the dose is recovered as unchanged carbamazepine. Half Life: Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Biological Half-Life The mean elimination half-life of carbamazepine was 35 to 40 hours after one dose of carbamazepine extended-release formulations. The half-life ranged from 12-17 hours after several doses of carbamazepine. One pharmacokinetic study determined the elimination half-life of carbamazepine to range between 27 to 36.8 hours in healthy volunteers. Initial single dose: May range from 25 to 65 hours. Chronic dosing: May decrease to 8 to 29 hours (average 12 to 17 hours) because of autoinduciton of metabolism. Carbamazepine-10,11-epoxide: 5 to 8 hours. /Carbamazepine-10,11-epoxide/ |
||
| Toxicity/Toxicokinetics |
Toxicity Summary Carbamazepine inhibits sustained repetitive firing by blocking use-dependent sodium channels. Pain relief is believed to be associated with blockade of synaptic transmission in the trigeminal nucleus and seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord. Carbamazepine also possesses anticholinergic, central antidiuretic, antiarrhythmic, muscle relaxant, antidepressant (possibly through blockade of norepinephrine release), sedative, and neuromuscular-blocking properties. Interactions Various combinations of carbamazepine, felbamate, and phenytoin were evaluated in mice (ip) for anticonvulsant activity (maximal electroshock seizure test) and minimal neurotoxicity (rotarod test). The results obtained from these studies were analyzed using response surface methodologies. The outcomes of these analyses in regard to anticonvulsant activity suggest that, under these experimental study conditions, at 0.5 hr post treatment there is a significant carbamazepine/phenytoin synergism even though none of the drugs has a significant dose-response by that time when given alone, and that at l.0 hr post treatment, the combination dose-response is additive. Thus, there appears to be an important dose/time relationship. In regard to the neurotoxic response, the results suggest a significant carbamazepine/phenytoin synergism at 0.25 hr post treatment and an additive neurotoxic effect due to the combination of felbamate/carbamazepine/phenytoin at 0.5, l.0 and 2.0 hr post exposure. Risk of hepatotoxicity with single toxic doses or prolonged use of high doses of acetaminophen may be increased, and therapeutic effects of acetaminophen may be decreased, in patients taking hepatic enzyme-inducing agents such as carbamazepine. Concurrent use /of aminophylline, oxtriphylline, or theophylline/ with carbamazepine may stimulate hepatic metabolism of the xanthines (except dyphylline), resulting in increased theophylline clearance. Concurrent use /of hydantoin anticonvulsants, succinimide anticonvulsants, barbiturates, benzodiazepines metabolized via hepatic microsomal enzymes, especially clonazepam, primidone, or valproic acid/ with carbamazepine may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of these medications because of induction of hepatic microsomal enzyme activity; monitoring of blood concentrations as a guide to dosage is recommended, especially when any of these medications or carbamazepine is added to or withdrawn from an existing regimen. Valproic acid may prolong the half-life and reduce the protein-binding of carbamazepine; the concentration of the active 10,11-epoxide metabolite may be increased. In addition, use of carbamazepine in combination with other anticonvulsants has been reported to be associated with an increased risk of congenital defects and with an alteration of thyroid function. For more Interactions (Complete) data for CARBAMAZEPINE (41 total), please visit the HSDB record page. |
||
| References |
[1]. Willow, M. and W.A. Catterall, Inhibition of binding of [3H]batrachotoxinin A 20-alpha-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol, 1982. 22(3): p. 627-35. [2]. Biphasic effects of carbamazepine on the dopaminergic system in rat striatum and hippocampus. Epilepsy Res, 1997. 28(2): p. 143-53. [3]. Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15. [4]. Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway. Br J Pharmacol. 2013 Jan;168(1):139-50. [5]. Carbamazepine attenuates inducible nitric oxide synthase expression through Akt inhibition in activated microglial cells. Pharm Biol. 2014 Nov;52(11):1451-9. [6]. Carbamazepine promotes liver regeneration and survival in mice. J Hepatol. 2013 Dec;59(6):1239-45. [7]. Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice. Acta Neuropsychiatr. 2014 Feb;26(1):29-34. |
||
| Additional Infomation |
Therapeutic Uses Analgesics, Non-Narcotic; Anticonvulsants Carbamazepine has been shown to be effective in certain psychiatric disorders including schizoaffective illness, resistant schizophrenia, and dyscontrol syndrome, associated with limbic system dysfunction. /NOT included in US or Canadian product labeling/ Carbamazepine is used for the detoxification of alcoholics. It has been found to be effective in rapidly relieving anxiety and distress of acute alcohol withdrawal and for such symptoms as seizures, hyperexcitability, and sleep disturbances. /NOT included in US product labeling/ Carbamazepine is used alone or with other agents such as clofibrate or chlorpropamide in the treatment of partial central diabetes insipidus. /NOT included in US or Canadian product labeling/ For more Therapeutic Uses (Complete) data for CARBAMAZEPINE (10 total), please visit the HSDB record page. Drug Warnings There have been a few cases of seizures and/or respiratory depression in neonates born to women receiving carbamazepine concomitantly with other anticonvulsant agents. A few cases of vomiting, diarrhea, and/or decreased feeding also have been reported in neonates born to women receiving carbamazepine; these symptoms may represent a neonatal withdrawal syndrome Carbamazepine should not be used prophylactically during long periods of remission in trigeminal neuralgia. Although carbamazepine has ... been reported to relieve dystonic attacks in children, reduce migraine attacks, and relieve intractable hiccups in some patients, its therapeutic efficacy in such cases has not been established. Carbamazepine is not indicated for atypical or generalized absence seizures (petit mal) or myoclonic or atonic seizures. For more Drug Warnings (Complete) data for CARBAMAZEPINE (30 total), please visit the HSDB record page. Pharmacodynamics **General effects** Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels. In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS). Carbamazepine has a narrow therapeutic index. **A note on genetic variation and carbamazepine use** In studies of Han Chinese ancestry patients, a pronounced association between the HLA-B*1502 genotype and Steven Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) resulting from carbamazepine use was observed. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 5 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.2324 mL | 21.1622 mL | 42.3245 mL | |
| 5 mM | 0.8465 mL | 4.2324 mL | 8.4649 mL | |
| 10 mM | 0.4232 mL | 2.1162 mL | 4.2324 mL |