Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy

Abstract

The kinetics of carbamazepine using 15N-carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N-carbamazepine plasma half-lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half-lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady-state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine-trans-diol, 5.2% to 8.8% as 9-hydroxymethyl-10-carbamoyl acridane, 1% to 1.4% as 10,-11-carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide-diol pathway which is induced during long-term treatment. Concomitant therapy with primidone, phenytoin, phenobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

Inhibitory and Inducing Effects of Denzimol on Carbamazepine Metabolism in the Rat

“…Although it cannot be ascertained that the enhanced elimination of this metabolite in denzimoltreated rats was due to induction of the epox ide-hydrolase, which is assumed to be the main enzyme responsible for conversion of the epoxide to its transdihydrodiol [23][24][25], this hypothesis is consistent with published reports that the epoxide-diol pathways may be induced during both auto-and hetero induction [23,26,27], Since, like the 10, 11-derivative, the other epoxides formed during the biotransformation of CBZ in the rat are metabolic intermediates [24], it is conceiv able that denzimol may act by inducing the formation and/or further elimination of each of these metabolites, although there is no evidence of the effect of denzimol on these pathways.…”

Interdosage Fluctuations in Plasma Carbamazepine Concentration Determine Intermittent Side Effects

“…Owing to autoinduction, however, plasma half-lives decrease to ten to 15 hours during carbamazepine mainte¬ nance therapy,3 with a further short¬ ening of half-lives to five to 13 hours in patients who have also been treated with other anticonvulsants, such as phenytoin sodium and phénobarbital sodium. 4 The increase in metabolism results in pronounced daily fluctua¬ tions in plasma carbamazepine con¬ centration in some patients receiving carbamazepine two or three times dai¬ ly, especially if they are receiving a combination therapy.5 7 Anecdotal re¬ ports on the association between peak plasma concentrations of carbamaze¬ pine and side effects are available,5·8·9 but a more systematic study of the relationship between fluctuations in plasma carbamazepine concentration and the occurrence of side effects has not been published to my knowledge.…”

Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters

“…Reactive electrophiles can potentially react with nucleic acids (DNA) and proteins, leading to mutagenic, toxic, and carcinogenic effects [86,87]. However, some epoxides are relatively stable at physiological pHs (i.e., carbamazepine-10,11-epoxide [88,89]), but they still may be associated with toxicity [90,91]. The addition of water to epoxides by EH to form the corresponding trans-dihydrodiols is one way in which the body can eliminate epoxides and is usually considered a detoxification pathway.…”