INTERACTIONS OF PHENOBARBITAL AND PHENYTOIN WITH CARBAMAZEPINE AND ITS METABOLITES CONCENTRATIONS, CONCENTRATION RATIOS, AND LEVEL DOSE RATIOS IN EPILEPTIC CHILDREN

The effects of phenytoin (PHT) or phenobarbital (PB) comedication on t he concentrations, concentration ratios, and level/dose ratios of carb amazepine (CBZ) and its metabolites were investigated. The heteroinduc tion effects of CBZ metabolism by PHT or PB were clearly demonstrated. Serum CBZ level/dose ratios in patients with CBZ polytherapy were dec reased while CBZ-10,11-epoxide (CBZ-E) and trans-10,11-dihydroxy-10,11 -dihydro-CBZ (CBZ-H) concentrations were increased as compared with th ose of patients receiving CBZ alone. The concentration ratios of CBZ-H /CBZ and CBZ-E/ CBZ were also greater in patients receiving CBZ + PHT or CBZ+PB than in patients receiving CBZ alone. In addition, positive correlations between serum PHT concentration and CBZ-H/CBZ or CBZ-E/CB Z concentration ratios were observed. There were no significant differ ences in CBZ-H/CBZ-E concentration ratios, the free fractions of CBZ a nd its metabolites, and CBZ-E or CBZ-H level/dose ratios among the thr ee groups of patients. Because this approach investigates the in vivo relation between the substrates and products of the enzymes involved i n CBZ biotransformation, more detailed information about the drug inte ractions was obtained. The results suggest that the PHT has a potent i nduction effect an CBZ epoxidase, whereas PB is a moderate inducer.