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 high-performance liquid chromatography in 435 specimens divided into two groups: CBZ monotherapy (n = 78) and CBZ polytherapy (n = 357). Distributions of concentrations of CBZ and its metabolites were derived, their protein binding investigated, and the differences of concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of sex, age, and comedication on CBZ metabolism. Concentrations of CBZ ranged from 2.5 to 82.9 mumol/L (mean +/- SD, 22.3 +/- 10.9 mumol/L), 73% being within the therapeutic range (17-51 mumol/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 mumol/L (mean +/- SD, 5.17 +/- 2.56 mumol/L), and those of CBZD were between 0.77 and 36.4 mumol/L (mean +/- SD, 11.3 +/- 5.4 mumol/L). A multiplicative regression best fitted the concentration/dose plots of CBZ and CBZE and an exponential regression for CBZD. Dose correlated best with the second biotransformation product, CBZD. Free fractions 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 disposition. A gradual, high-amplitude age increase of CBZ dose ratio was observed in the monotherapy group, with global difference of approximately 3.6 times, while CBZE dose ratio increased approximately 2-fold, and CBZD dose ratio increased to the smallest extent of 1.5 times. In the polytherapy group, a smaller global age increase for CBZ dose ratio of 3.4 times was found, but the respective increase for dose ratios of metabolites was greater compared with the monotherapy patients: 2.3 times for CBZE and 1.8 times for CBZD. Comedication of other antiepileptic drugs induced significant decrease of CBZ dose ratio only, but no changes of dose ratios of the metabolites were registered. The influence of valproic acid was represented in a particular pattern. We conclude that 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.
Svinarov
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DA
Department of Clinical Laboratory, Alexander Hospital, Faculty of Medicine, Sofia, Bulgaria.
Pippenger
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CE
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000097:blood* / Q000627:therapeutic use; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000627:therapeutic use; D011485:Protein Binding; D012737:Sex Factors
D000927:Anticonvulsants; D002220:Carbamazepine; C004822:10,11-dihydro-10,11-dihydroxy-5H-dibenzazepine-5-carboxamide; C012227:carbamazepine epoxide; D010634:Phenobarbital