Improved therapeutic monitoring of drug interactions in epileptic children using carbamazepine polytherapy

Drug interactions in epileptic children with carbamazepine (CBZ) polytherapy were investigated by analysis of total and free CBZ and its metabolites simultaneously. Heteroinduction effects of CBZ metabolism by other antiepileptic drugs (AEDs), including phenytoin (PHT), phenobarbital (PB), or primidone (PRM), were clearly demonstrated. Serum CBZ level/dose ratios in patients taking CBZ plus other AEDs were decreased while CBZ-10, 11-epoxide (CBZ-E) and trans-10,ll-dihydroxy-10,ll-dihydro-CBZ (CBZ-H) concentrations were significantly increased compared to patients with CBZ alone. Concentration ratios of CBZ-H/CBZ and CBZ-E/CBZ were also significantly higher in patients taking CBZ plus other AEDs. Interactions between CBZ and valproic acid (VPA) involved both protein binding displacement and metabolic inhibition. Patients taking CBZ plus VPA showed significantly increased free fractions of CBZ and CBZ-E and substantially increased serum CBZ-E concentrations and CBZ-E level/dose ratios, while CBZ-H/CBZ-E concentration ratios were decreased compared with patients on CBZ alone. Since this approach investigates the in vivo relationship between substrates and products of the enzymes involved in CBZ biotransformation (the ratios between CBZ and its metabolites), detailed information about the activities of the enzymes may be obtained. This approach appears to be a practical way to improve the monitoring of CBZ metabolism influenced by various physiological or pathological conditions and achieve a better understanding of the drug interactions under different drug regimens (coadministered inhibitor or inducer). This principle may also be adopted for other drugs with similar metabolic characteristics.