Carbamazepine-10,ll-epoxide

Clinically significant interactions can be caused by inhibitors of epoxide hydrolase, such as valpromide and valnoc-tamide, which increase the serum concentrations of the active metabolite carbamazepine-10,ll-epoxide. 

The pharmacokinetic interaction of nefazodone 200 mg bd with steady-state carbamazepine has been investigated in 12 healthy men (103). Nefazodone increased the steady-state plasma AUC of carbamazepine by 23% and reduced the AUC of active carbamazepine-10,ll-epoxide by 20%. The steady-state AUC of nefazodone fell 14-fold and the AUCs of its metabolites (hydroxynefazodone, metachlorophenylpiperazine, and triazoledione) also fell significantly. Thus nefazodone had a small inhibitory effect on carbamazepine metabolism, while carbamazepine greatly increased the metabolism of nefazodone. 

Yoshimura R, Nakamura J, Eto S, Ueda N. Possible relationships between plasma carbamazepine-10,ll-epoxide levels and antimanic efficacy and side effects in patients with schizoaffective disorde. Hum Psychopharmacol 2000 15(4) 237 0. 

In patients taking carbamazepine, valproate slightly increases the serum concentration of the active metabolite carbamazepine-10,ll-epoxide, by inhibiting epoxide hydrolase and perhaps also by inhibiting the glucuronida-tion of carbamazepine-10,ll-trans-diol (128). 

Valpromide is a more potent inhibitor than valproate of carbamazepine epoxide hydrolase in vitro (129) and in six healthy volunteers it caused a marked rise in carbamazepine-10,ll-epoxide, prolonging the half-life of carbamazepine-10,ll-epoxide from 6.4 to 21 hours and reducing its clearance three-fold, suggesting that valpromide inhibits epoxide hydrolase in the liver in vivo as well as in vitro, despite the fact that it is rapidly converted in vivo to valproate (130). 

In 12 adults with epilepsy taking carbamazepine, valpromide produced a larger increase in plasma concentrations of carbamazepine-10,ll-epoxide than valproate (131). 

In healthy subjects valnoctamide 200 mg tds for 8 days prolonged the half-life of carbamazepine-10,ll-epoxide from 7 to 20 hours and reduced its oral clearance fourfold, suggesting that valnoctamide, like its isomer valpromide, is a potent inhibitor of carbamazepine epoxide hydrolase (130). 

Lanchote, V.L. Bonato, P.S. Campos, G.M. Rodrigues, I. Factors influencing plasma concentrations of carbamazepine and carbamazepine-10,ll-epoxide in epileptic children and adults. Ther.DrugMonit, 1995, 17, 47-52... 

Simultaneous metabolites, carbamazepine-10,ll-epoxide, carbamazepinediol, felbamate,... 

Neels, H.M. Totte, J.A. Verkerk, R.M. Vlietinck, A.J. Scharpe, S.L. Simultaneous high performance liquid-chromatographic determination of carbamazepine, carbamazepine-10,ll-epoxide, ethosuximide, phenobarbital, phenytoin, primidone and phenylethylmalonamide in plasma. J.Clin. Chem.Clin.Biochem., 1983, 21, 295-299... 

Pitterle ME, Collins DM. Carbamazepine-10,ll-epoxide evaluation associated with coadministration of loxitane or amoxapine. Epilepsia (1988) 29,654. 

A study in 8 patients with epilepsy taking carbamazepine found that oral ketoconazole 200 mg daily for 10 days increased their serum carbamazepine levels by 28.6% (from 5.6 to 7.2 micrograms/mL) without affecting carbamazepine-10,ll-epoxide levels. When the ketoconazole was stopped the serum carbamazepine levels returned to their former levels. ... 

Some reports describe rises in serum phen 4oin levels, with toxicity, whereas others describe falls in phen i oin levels. Genetic differences in the metabolism of these drugs may be an explanation for the differences. Falls in carbamazepine serum levels, sometimes with rises in carbamazepine-10,ll-epoxide levels, have been described. 

Simultaneous carbamazepine-10,ll-epoxide, clonazepam, dihydrodihydroxycarbamaze-pine, hexobarbital, p-hydro gfphenobarbital, 5-(m-hydrosyphenyl)-5-phenylhydantoin, 5-(p-hydro Qrphenyl)-5-phenylhydantoin, nitrazepam, phenobarbital, phenylethylmaleimide, phenytoin, primidone... 

Metabolism hepatic (98%) via cytochrome P450 isoenzyme CYP3A4. Dining prolonged treatment, carbamazepine induces its own metabolism. Active metabolites carbamazepine-10,ll-epoxide (CBZ-E). 

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. 

Omzigt JGC, Los FJ, Meijer JWA, et al. The 10,ll-epoxide-10,ll-diol pathway of carbamazepine in early pregnancy in maternal serum, urine, and amniotic fluid effect of dose, comedication, and relation to outcome of pregnancy. Ther Drug Monit 1993 15 1-10. 

Extracted metabolites, carbamazepine-10,11-epoxide, carbamazepine-10,ll-trans-diol... 

In a multiple-dose study, St John s wort had no effect on the pharmacokinetics of carbamazepine or its metabolite (carbamazepine-10,ll-epox-ide) in 8 healthy subjects. In this study, subjects took carbamazepine 200 mg increased to 400 mg daily alone for 20 days, then with St John s wort 300 mg (standardised to 0.3% hypericin) three times daily for a further 14 days. In contrast, the AUC of a single 400-mg dose of carbamazepine was reduced by 21% after St John s wort 300 mg was given three times daily for 14 days, and the AUC of the 10,11-epoxide metabolite was increased by 26%. ... 

Oxcarbazepine. Oxcarbazepine (10,11-dihydro-10-oxo-5i -dibenz [6,/] azepine-5-car-boxamide or 10,ll,dihydro-10-oxo carbamazepine, 12) was designed to avoid the dose-dependent side effects noted in some patients (e.g., nausea, headache, dizziness, ataxia, diplopia) and to minimize enzyme induction and drug-drug interactions displayed by carbamazepine (195,196). As shown previously (Fig. 6.3), the change in structure results in a difference in metabolism. Although both carbamazepine and oxcarbazepine are ultimately converted to the inactive trans diol, oxcarbazepine does not form the active 10,11-epoxide intermediate, but does form the active 10-hydroxy metabolite MHD (197). The mechanism of action of oxcarbazepine is very similar... 

Sawchuk RJ, Cartier LL (1982) Simultaneous liquid-chromatographic determination of carbamazepine and its epoxide metabolite in plasma. Clin Chem 28 2127-2130... 

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