Carbamazepine-10,11 -diol

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

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. 

D. A. Svinarov, C. E. Pippenger, Relationships between Carbamazepine-Diol, Carba-mazepine-Epoxide, and Carbamazepine Total and Free Steady-State Concentrations in Epileptic Patients The Influence of Age, Sex, and Comedication , Ther. Drug Monit. 1996,18, 660 - 665. 

Extracted metabolites, carbamazepine diol, carbamazepine epoxide, 5-(p-hydroxyphenyl)-... 

Extracted amobarbital, barbital, butabarbital, caffeine, carbamazepine, carbamazepine diol, carbamazepine epoxide, chloramphenicol, ethosuximide, glutethimide, mephenytoin, methaqualone, methyprylon, nirvanol, pentobarbital, phenacemide, phenobarbital, primidone, secobarbital, theophylline... 

Sample preparation 500 pL Serum + 600 pL allobarbited in 75 mM pH 6.8 phosphate buffer, add 200 units p-glucuronidase, heat at 37°for 30 min, add 1 mL of this solution to an Extrelut-1 SPE cartridge, let stand for 10 min, elute with 2.5 mL MTBE. Evaporate the eluate to dr3mess under a stream of nitrogen, reconstitute the residue in 50 pL MeOH water 50 50, inject a 10 pL aliquot onto columns A and B in series and elute with mobile phase A. After 12 min elute column A with mobile phase B, continue to elute column B with mobile phase A. Carbamazepine diol, carbamazepine epoxide, phenytoin, and carbamazepine elute from column A and the enantiomers of 5-(p-hydroxyphenyl)-5-phenyUiydantoin and mephobarbital, phenobarbital, zonisamide, and allobarbital elute from column B. Re-eqviilibrate columns A and B with mobile phase Afor 5 min before the next injection. 

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. 

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. 

As a metabolic pathway, alkene oxidation is not common. When an alkene is oxidized, an epoxide forms. The epoxide normally reacts with water and opens to a 1,2-diol. The alkene in carbamazepine (8.20) is oxidized to a small degree to form the corresponding epoxide (8.21) (Scheme 8.7). 

Hydration, in the context of metabolism, is the addition of water to a structure. Epoxides are readily hydrated to diols (see carbamazepine, Table 9.1), the reaction being catalysed by the enzyme epoxide hydrolase. 

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. 

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). 

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... 

Another important group of hydrolytic enzymes are the epoxide hydrolases, also known as epoxide hydrase or epoxide hydratase, most commonly found in liver tissue. Epoxide hydrolases catalyze the hydration of arene oxides and aliphatic epoxides to their corresponding /raKt-dihydrodiols or diols, respectively, by activating a water molecule to attack one of the carbons of the arene oxide or epoxide [41]. Although one of the major metabolites of carbamazepine is the stable epoxide, this metabolite also undergoes hydrolysis to form the trans-dial metabolite (Fig. 3). Likewise, the anticonvulsants phenytoin and mephenytoin form arene oxides, which then form trans-dihy-drodiol that undergo further oxidation to form the catechols by the enzyme dihydrodiol dehydrogenase (Fig. 11) [42,43]. 

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

CYPs are good at epoxidizing aikenes and alkynes as well, which is probably one reason why more drugs don t contain these groups. Then again, just because a reaction can happen doesn t mean that it will. For carbamazepine (Figure 9.18), epoxidation followed by diol formation is the major metabolic route, but for tamoxifen, metabohc epoxidation of the central double bond hardly happens, and other CYP-catalyzed reactions, including arene epoxidation and N-demethylation (discussed in a later section) are much more in evidence. 

Danazol inhibits the metabolism (by the epoxide-trans-diol pathway) of carbamazepine by the liver, thereby reducing its loss from the body. During danazol treatment the clearance of carbamazepine has been found to be reduced by 60%. ... 

Rambeck B, May T, Juergens U. Serum concentrations of carbamazepine and its epoxide and diol metabolites in epileptic patients the influence of dose and comedication. TherDrugMonit (1987) 9, 298-303. 

Sunaoshi W, Miura H, Takanashi S, Shira H, HosodaN. Influence of concurrent administta-tion of sodium valproate on the plasma concentrations of carbamazepine and its epoxide and diol metabolites. JpnJPsychiatry Neurol (1991) 45, 474-7. 

The topiramate plasma levels and AUC were found to be about 40% lower in the presence of carbamazepine in a study in 12 epileptic patients. A population pharmacokinetic study reported that patients taking carbamazepine had 32% lower morning topiramate level than patients not taking enzyme-inducing antiepileptics. In a study in healthy subjects carbamazepine 600 mg daily was found to cause a twofold increase the clearance of a single 200-mg dose of topiramate. The mean half-life of topiramate decreased from 29 to 19 hours. There was also a two- to threefold increase in the formation of the 2 major metabolites of topiramate (2,3-diol-TPM and 10-OH-TPM), although 41% of topiramate was excreted unchanged in the urine in the presence of carbamazepine. In contrast, an earlier study reported that carbamazepine did not have a major effect on the pharmacokinetics of topiramate. ... 

The epoxide metabolites of alkenes tend to be more stable than arene oxides. They undergo ring opening with water to give diols. One example of this type of reaction is the ring opening of the epoxide of the anticonvulsant drug carbamazepine. 

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