Effect of valproate and felbamate on carbamazepine and its metabolites in epileptic children

The metabolism of carbamazepine (CBZ) has been reported to be influenced by comedication with both valproate (VPA) and felbamate (FBM). We replaced VPA with FBM in a group of four patients receiving VPA and CBZ who failed to achieve satisfactory seizure control and/or experienced side effects. In the process of tapering VPA and initiating FBM, we conducted serial therapeutic drug monitoring to investigate the drug interactions. As compared with baseline levels, CBZ and its metabolite concentrations were all decreased. The levels of CBZ were decreased by 25-31%, whereas carbamazepine-10,11- epoxide (CBZ-E) concentrations were lower by more than 55%. The trans-10,11- dihydroxy-10,11-dihydro-CBZ (CBZ-H) concentrations were slightly decreased. Both CBZ-H/CBZ-E and CBZ-H/CBZ concentration ratios were increased, while CBZ-E/CBZ concentration ratios were decreased. These results suggest that the biotransformation of CBZ-E to CBZ-H is increased during the process of tapering VPA, presumably due to the release of the inhibitory effect on liver epoxide-hydrolase by the reduction of VPA doses. The most likely mechanism for the decreased CBZ levels appears to be the induction of CBZ metabolism produced by introducing FBM. These drug interactions and the potential clinical consequence should be monitored and correctly interpreted, since both CBZ and CBZ-E are active in the treatment of seizures.