Dual Effects of Carbamazepine-Phenytoin Interaction

By intrapatient comparison at constant phenytoin (PHT) dose, the effect of increased carbamazepine (CBZ) dose was studied in 32 epileptic outpatients treated with a combination of PHT and CBZ. The mean PHT plasma concentration, as well as the concentration/dose ratio for PHT, became significantly higher secondary to increased doses of CBZ (14.1 +/- 3.5 vs. 19.3 +/- 3.6 micrograms/ml and 2.8 +/- 1.0 vs. 3.9 +/- 1.4 micrograms/ml plasma per milligram/kilogram daily dose, respectively; p less than 0.001). Concomitantly, in spite of CBZ dose higher by 17.6%, the CBZ concentration increased by only 6.4%, and the CBZ concentration/dose ratio actually decreased by 10%. In contrast, by intrapatient comparison at constant CBZ dose, the effect of reduced PHT dose on CBZ was studied in 22 patients. The mean CBZ plasma concentration as well as the concentration/dose ratio for CBZ appeared significantly higher, with a concomitant reduction of PHT (6.7 +/- 1.6 vs. 8.6 +/- 1.6 micrograms/ml and 0.37 +/- 0.1 vs. 0.49 +/- 0.2 micrograms/ml plasma per milligram/kilogram daily dose, respectively; p less than 0.001). This simultaneous dual effect--inhibition of PHT metabolism by CBZ and induction of CBZ metabolism by PHT--can result in PHT intoxication along with a fall in CBZ plasma concentration to a subtherapeutic range. This effect may be avoided or reduced if the PHT concentration is adjusted to approximately 13 micrograms/ml before CBZ is added or increased.