Carbamazepine 10,11-epoxide

The liver metabolizes 98% to 99% of a dose of carbamazepine (mostly by CYP3A4), and the major metabolite is carbamazepine-10,11-epoxide, which is active. 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

Interestingly, there is a marked species difference in the in vitro hydrolysis of carbamazepine 10,11-epoxide, such that the reaction was observed only in liver microsomes from humans but not in liver microsomal or cytosolic preparations from dogs, rabbits, hamsters, rats, or mice [181][196], Thus, carbamazepine appears to be a very poor substrate for EH, in analogy with the simpler analogues 10.129 (X = RN, RCH, or RCH=C). The human enzyme is exceptional in this respect, but not, however, in the steric course of the reaction. The diol formed (10.131, X = H2NCON) is mostly the trans-(10.S, 11. S )-enaniiomer [196], In other words, the product enantioselectivity of the hydration of carbamazepine epoxide catalyzed by human EH is the same as that of di benzol a,oxide catalyzed by rabbit microsomal EH, discussed above. 

Children In children younger than 15 years of age, there is an inverse relationship between carbamazepine-10,11-epoxide/carbamazepine ratio and increasing age. The safety of carbamazepine in children has been studied up to 6 months of age. 

Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own. 

Oxidation Athene Epoxidation. Alkenes may react to produce epoxides (alternatively, sometimes, the alkenes do not react and are metabolically stable). The epoxide is unstable and is subject to ring opening via a nucleophilic attack. The anticonvulsant drug carbamazepine is metabolized via epoxidation to yield carbamazepine-10,11-epoxide in turn, this is rapidly opened to yield carbamazepine-10,ll-diol. 

Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. Clin Pharmacokinei 1986 11 177-198. 

Carbamazepine is completely metabolized in humans to several derivatives. One of these, carbamazepine-10,11-epoxide, has been shown to have anticonvulsant activity. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown. 

Primidone - Phenobarbitone and phenylethylmalonamide Carbamazepine - Carbamazepine 10,11-epoxide Trimethadione - Dimethadione (long half-life)... 

Antiepileptic drugs (ethosuc- Spherisorb ODS-1, 3 pm cinimide, primidon, carbamazepine-10,11 -diol, carbamazepine-10,11-epoxide, carbamazepine, phenytoin... 

Negative myoclonus and more typical signs of carbamazepine intoxication (fatigue, ataxia, clumsiness) occurred in a 66-year-old man after he took add-on clobazam (10 mg/day) for 4 weeks (14). Plasma concentrations of carbamazepine (58 pmol/1) and carbamazepine-10,11-epoxide (19 pmol/1) were higher than before clobazam therapy, and his symptoms resolved quickly when carbamazepine dosage was reduced and clobazam was withdrawn. The interaction was confirmed on rechallenge. 

Carbamazepine (antiepileptic) + metabolites carbamazepine-10,11-epoxide (CEO), acridine (ACR)... 

Carbamazepine and its metabolites were investigated in hair samples of 30 epileptics by Rothe et al. using GC/MS. The concentrations ranged from 7.6 to 205 ng/mg for carbamazepine and from 1.1 to 23 ng/mg for carbamazepine-10,11-epoxide. No significant correlation was found between these hair concentrations and the daily dosage of carbamazepine, leading the authors to consider the investigation of hair samples not suitable for compliance analysis. 

Retrospective studies suggest linear correlation between sum of plasma carbamazepine and carbamazepine-10,11-epoxide and therapeutic effect. 

Gas Chromatography. System GA—carbamazepine RI 2290, carbamazepine-10,11-epoxide RI 2030, iminostilbene RI 1930 system GE—carbamazepine retention time 0.83 relative to phenytoin system GF—carbamazepine RI 2610, carbamazepine-10,11-epoxide RI 2560, iminostilbene RI 2620. 

Quantification. Gas Chromatography. In plasma carbamazepine and carbamazepine-10,11-epoxide, FID—A. Ranise et al., J. Chromat., 1981, 222 Biomed. AppL, 11, 120-124. In plasma or urine carbamazepine. and other anticonvulsants. 

High Pressure Liquid Chromatography. In plasma or saliva carbamazepine and carbamazepine-10,11-epoxide, sensitivity 20 ng/ml for carbamazepine and 120 ng/ml for the metabolite in plasma, UV detection—J. J. MacKichan, J. Chromat., 1980, 18F, Biomed. AppL, 7, 373-383. In plasma or serum carbamazepine and other anticonvulsants, sensitivity about 1 ig/ml, UV detection—J. A. Christofides and D. E. Fry, Clin. Chem., 1980, 26, 499-501. 

Major metaboiite (carbamazepine-10,11 epoxide) may be the cause of many side effects... 

In seven lactating women the mean concentrations of carbamazepine in milk and plasma samples were 15 and 26 pmol/l respectively the concentrations of carbamazepine 10,11-epoxide were 5 and 8 qmol/1 respectively (75). The mean milk/plasma ratios were 0.64 and 0.79 respectively. The amounts of carbamazepine and carbamazepine 10,11-epoxide that a breast-feeding child is likely to consume are thus very small. 

The relations between plasma concentrations of carbamazepine and its two major metabolites, carbamazepine-10, 11-epoxide and carbamazepine-10,11-diol, and antimanic efficacy and adverse effects in patients with schizoaffective disorder have been studied in 10 patients (81). There were positive relations between plasma concentrations of the epoxide and the degree of clinical improvement and adverse effects, but not with plasma concentrations of carbamazepine or its diol. 

Shimoyama R, Ohkubo T, Sugawara K. Monitoring of carbamazepine and carbamazepine 10,11-epoxide in breast milk and plasma by high-performance hquid chromatography. Ann Clin Biochem 2000 37(Pt 2) 210-15. 

Felbamate is a metabolic inhibitor and significantly increases blood concentrations of carbamazepine-10,11-epoxide (SEDA-19, 69) (SEDA-20, 61). 

Pisani F, Fazio A, Artesi C, Oteri G, Spina E, Tomson T, Perucca E. Impairment of carbamazepine-10, 11-epoxide eUmination by valnoctamide, a valpromide isomer, in healthy subjects. Br J Clin Pharmacol 1992 34(l) 85-7. 

Main metabolite (carbamazepine-10,11-epoxide) of carbamazepine. "As an anticoagulant for plasma separation. 

A Frigerio, R Fanelli, P Biandrate, G Passerini, PL Morselli, S Garaattini. Mass spec-trometric characterization of carbamazepine-10,11-epoxide, a carbamazepine metabolite isolated from human urine. J Pharm Sci. 61 1144—1147,1972. 

Although widely regarded by British psychiatrists as a safer alternative to lithium, carbamazepine has a range of potentially serious side-effects and patient tolerance is poor (Table 5.3). Many of the autoimmune effects are thought to be related to the metabolite carbamazepine-10, 11-epoxide. 

It is not metabolised to carbamazepine-10,11-epoxide and lacks the same propensity... 

Phenobarbitone, phenyltoin nitrazepam, carbamazepine and its metabolite, carbamazepine-10, 11-epoxide Adsorption Lichrosorb SI 100 Dichloromethane/ tetrahydrofuran... 

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