Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Abstract

Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 mumol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of valpromide on the pharmacokinetics of carbamazepine‐10, 11‐ epoxide.

“…Since the latter is cleared virtually entirely by conversion to the corresponding diol by epoxide hydrolase (Tomson et al, 1983;Bertilsson & Tomson, 1986), our data can be regarded as strong for evidence for the occurrence of in vivo inhibition of this enzyme. Such a mechanism of interaction is further supported by increased plasma levels of CBZ-E during combined therapy with CBZ and VPM (Meijer etal., 1985;Pisani et al, 1986) and by in vitro experiments showing that VPM is a powerful inhibitor of epoxide hydrolase in monkey (Pacifici et al, 1985) and human (Pacifici et al, 1986) liver microsomes.…”

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

“…However, it should be noted that carbamazepine treatment with a longer period may further induce the metabolism of alprazolam, because the enzyme-inducing effect of carbamazepine appears to be maximal at 3-5 weeks (Bertilsson and Tomson 1986).…”

Single and multiple dose pharmacokinetics of tenidap sodium in healthy subjects.

“…The phenomenon of auto-induction has been observed with other drugs. For example, the anti-epileptic carbamazepine is extensively metabolised in the liver, and can induce its own metabolism such that repeated administration results in a reduced plasma half-life [22].…”