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Clinical Pharmacokinetics of Carbamazepine

Abstract

Carbamazepine seems to be as effective as phenytoin in the treatment of grand mat and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia.

After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10–20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics.

Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10, 11 -epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine dose has been identified as metabolites in the urine. The quantitatively most important metabolite is the trans-10, 11-dihydro-10, 11-diol.

The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults.

A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects.

Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10μ/ml (20 to 40μmol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

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Bertilsson, L. Clinical Pharmacokinetics of Carbamazepine. Clin Pharmacokinet 3, 128–143 (1978). https://doi.org/10.2165/00003088-197803020-00003

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Keywords

  • Carbamazepine
  • Epoxide
  • Clinical Pharmacology
  • Antiepileptic Drug
  • Clinical Pharmacokinetic