Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants.

Brodie, MJ; Forrest, Gerard; Rapeport, WG

doi:10.1111/j.1365-2125.1983.tb02257.x

Cited by 58 publications

(39 citation statements)

References 14 publications

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“…values for saliva CBZ-E/CBZ ratios, 0.40 + 0.21 (using AUC derived data) and 0.41 ± 0.24 using all data points are similar to those reported by Mackichan et al (1981). If CBZ and CBZ-E possess equipotent anticon- Brodie et al (1983), there was no significant relationship in this study between CBZ concentration and CBZ-E/CBZ ratio and our findings have not confirmed the significant correlation between CBZ and CBZ-E concentrations reported by Rane et al (1976).…”

Section: Resultssupporting

confidence: 81%

Carbamazepine 10,11‐epoxide in children.

Rylance¹,

Edwards²,

Gard³

1984

Brit J Clinical Pharma

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1 Concentrations of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were measured in simultaneously collected plasma and mixed saliva samples from 15 children (aged 1-13 years). 2 Saliva concentrations of CBZ and CBZ-E were measured in hourly samples taken from six of these children during dose intervals whilst on different dose or dosefrequency regimens. 3 Saliva and plasma CBZ (r = 0.91; P< 0.001) and CBZ-E (r = 0.91; P < 0.001) concentrations were significantly correlated. 4 The mean + s.d. steady state CBZ-E/CBZ concentration ratio in the six children was 0.40 + 0.21 and was similar at all times within the 12 h dose interval.5 The mean + s.d. percentage fluctuation of the combined CBZ + CBZ-E (103.0± 28.9) was significantly less than that of CBZ-E (145.5 + 52.8) but not CBZ (109.6+ 31.1). 6 If CBZ and CBZ-E have equipotent anticonvulsant activity in man, the contribution of CBZ-E approximates to 30% of total anticonvulsant effect in children taking CBZ alone.

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Section: Resultssupporting

confidence: 81%

Carbamazepine 10,11‐epoxide in children.

Rylance¹,

Edwards²,

Gard³

1984

Brit J Clinical Pharma

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“…The coadministration of valproic acid (VPA) with carbamazepine (CBZ) has been found to increase the concentration of relative to that of CBZ in patients (McKauge et al, 1981;Brodie et al, 1983;Levy et al, 1984). The epoxide, a stable metabolite of CBZ, is converted by epoxide hydrolase to a terminal trans-dihvdrodiol product (Tomson et al, 1983).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.

Robbins

Wedlund

Kuhn

et al. 1990

Brit J Clinical Pharma

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The effect of valproic acid (VPA) on the disposition of carbamazepine-10,11-epoxide (epoxide) was studied in five epileptic patients on chronic carbamazepine (CBZ) therapy. The individual pharmacokinetic parameters influencing epoxide disposition were determined in the presence and absence of VPA. VPA significantly decreased the clearance of unbound epoxide (an in vivo index of epoxide hydrolase activity), but did not appear to affect epoxide formation. VPA also increased the free concentrations of both CBZ and epoxide.

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“…CBZ is an enzyme inducer, and its own metabolism is susceptible to autoinduction after repeated administration. VPA increases the plasma concentration of the epoxide metabolite by inhibiting epoxide hydrolase, without any marked changes in the concentration of CBZ (76)(77)(78). The clinical significance of this interaction is particularly important in children, in whom concentrations of epoxide of Յ13 g/ ml have been observed, along with severe side effects such as vomiting and tiredness (79).…”

Section: Carbamazepine Coadministered With Valproatementioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants.

Cited by 58 publications

References 14 publications

Carbamazepine 10,11‐epoxide in children.

Carbamazepine 10,11‐epoxide in children.

Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.

The Importance of Drug Interactions in Epilepsy Therapy

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