RELATIONSHIPS BETWEEN CARBAMAZEPINE-DIOL, CARBAMAZEPINE-EPOXIDE, AND CARBAMAZEPINE TOTAL AND FREE STEADY-STATE CONCENTRATIONS IN EPILEPTIC PATIENTS - THE INFLUENCE OF AGE, SEX, AND COMEDICATION

Steady-state plasma carbamazepine (CBZ), carbamazepine-epoxide (CBZE), and carbamazepine-diol (CBZD) concentrations were quantified by highp erformance liquid chromatography in 435 specimens divided into two gro ups: CBZ monotherapy (n = 78) and CBZ polytherapy (n = 357). Distribut ions of concentrations of CBZ and its metabolites were derived, their protein binding investigated, and the differences of concentration/dos e (mu mol/L/mg/kg/day or 1/clearance) ratios were calculated as a meas ure for the influence of sex, age, and comedication on CBZ metabolism. Concentrations of CBZ ranged from 2.5 to 82.9 mu mol/L (mean +/- SD, 22.3 +/- 10.9 mu mol/L), 73% being within the therapeutic range (17-51 mu mol/L), 24% being less than the therapeutic range, and 3% greater than the therapeutic range. Concentrations of CBZE ranged from 0.85 to 16.6 mu mol/L (mean +/- SD, 5.17 +/- 2.56 mu mol/L), and those of CBZ D were between 0.77 and 36.4 mu mol/L (mean +/- SD, 11.3 +/- 5.4 mu mo l/L). A multiplicative regression best fitted the concentration/dose p lots of CBZ and CBZE and an exponential regression for CBZD. Dose corr elated best with the second biotransformation product, CBZD. Free frac tions were 0.22 +/- 0.03 for CBZ, 0.40 +/- 0.06 for CBZE, and 0.68 +/- 0.11 for CBZD. Sex was found to be of minor importance for CBZ dispos ition. A gradual, high-amplitude age increase of CBZ dose ratio was ob served in the monotherapy group, with global difference of similar to 3.6 times, while CBZE dose ratio increased similar to 2-fold, and CBZD dose ratio increased to the smallest extent of 1.5 times. In the poly therapy group, a smaller global age increase for CBZ dose ratio of 3.4 times was found, but the respective increase for dose ratios of metab olites was greater compared with the monotherapy patients: 2.3 times f or CBZE and 1.8 times for CBZD. Comedication of other antiepileptic dr ugs induced significant decrease of CBZ dose ratio only, but no change s of dose ratios of the metabolites were registered. The influence of valproic acid was represented in a particular pattern. We conclude tha t these findings could provide valuable information for CBZ metabolism and disposition in epileptic patients with respect to the efforts to ensure the best possible individualization of CBZ therapy.