EFFECT OF VALPROATE AND FELBAMATE ON CARBAMAZEPINE AND ITS METABOLITES IN EPILEPTIC CHILDREN

The metabolism of carbamazepine (CBZ) has been reported to be influenc ed by comedication with both valproate (VPA) and felbamate (FBM). We r eplaced 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 c onducted serial therapeutic drug monitoring to investigate the drug in teractions. As compared with base-line 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 we re 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 concent ration ratios were decreased. These results suggest that the biotransf ormation 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 mecha nism for the decreased CBZ levels appears to be the induction of CBZ m etabolism produced by introducing FBM. These drug interactions and the potential clinical consequence should be monitored and correctly inte rpreted, since both CBZ and CBZ-E are active in the treatment of seizu res. (C) 1997 by Elsevier Science Inc.