BACKGROUND AND OBJECTIVES: Oxcarbazepine is a new antiepileptic drug which in humans acts as a prodrug to its central nervous system-active metabolite 10-hydroxycarbazepine. Because 10-hydroxycarbazepine is a chiral molecule, the objective of the study was to perform a stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine in humans. METHODS: The pharmacokinetics and disposition of the enantiomers of 10-hydroxycarbazepine were investigated in 12 healthy Chinese subjects. Each subject received a single oral dose of 600 mg oxcarbazepine and the concentrations of R- and S-10-hydroxycarbazepine in serum were determined by a stereoselective HPLC assay. The enantiomers of free and conjugated 10-hydroxycarbazepine and of the oxidized diol metabolite were also quantified in urine. (con 't on page 548) RESULTS: At all sampling times, the serum concentrations of S-10-hydroxycarbazepine were much higher than those of R-10-hydroxycarbazepine, and their ratio also tended to increase with time. The area under the serum concentration versus time curve of S-10-hydroxycarbazepine was about fivefold greater than that of R-10-hydroxycarbazepine (129.8 +/- 33.1 versus 26.3 +/- 8.5 mg/L x h; P < .001). Half-lives did not differ significantly between the enantiomers (11.9 +/- 3.3 hours for R-10-hydroxycarbazepine versus 13.0 +/- 4.1 hours for S-10-hydroxycarbazepine). About 27% of the molar dose of oxcarbazepine was recovered in urine, mostly as the S-enantiomer of 10-hydroxycarbazepine and its conjugates. Carbamazepine-10,11-trans-dihydrodiol accounted for less than 3% of urinary metabolites. CONCLUSIONS: The marked differences in serum levels and urinary excretion between the two enantiomers of 10-hydroxycarbazepine are likely to be related primarily to stereoselective presystemic metabolic keto-reduction of the prochiral carbonyl group of the oxcarbazepine molecule.
BACKGROUND AND OBJECTIVES:Oxcarbazepine is a new antiepileptic drug which in humans acts as a prodrug to its central nervous system-active metabolite 10-hydroxycarbazepine. Because 10-hydroxycarbazepine is a chiral molecule, the objective of the study was to perform a stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine in humans. METHODS: The pharmacokinetics and disposition of the enantiomers of 10-hydroxycarbazepine were investigated in 12 healthy Chinese subjects. Each subject received a single oral dose of 600 mg oxcarbazepine and the concentrations of R- and S-10-hydroxycarbazepine in serum were determined by a stereoselective HPLC assay. The enantiomers of free and conjugated 10-hydroxycarbazepine and of the oxidized diol metabolite were also quantified in urine. (con 't on page 548) RESULTS: At all sampling times, the serum concentrations of S-10-hydroxycarbazepine were much higher than those of R-10-hydroxycarbazepine, and their ratio also tended to increase with time. The area under the serum concentration versus time curve of S-10-hydroxycarbazepine was about fivefold greater than that of R-10-hydroxycarbazepine (129.8 +/- 33.1 versus 26.3 +/- 8.5 mg/L x h; P < .001). Half-lives did not differ significantly between the enantiomers (11.9 +/- 3.3 hours for R-10-hydroxycarbazepine versus 13.0 +/- 4.1 hours for S-10-hydroxycarbazepine). About 27% of the molar dose of oxcarbazepine was recovered in urine, mostly as the S-enantiomer of 10-hydroxycarbazepine and its conjugates. Carbamazepine-10,11-trans-dihydrodiol accounted for less than 3% of urinary metabolites. CONCLUSIONS: The marked differences in serum levels and urinary excretion between the two enantiomers of 10-hydroxycarbazepine are likely to be related primarily to stereoselective presystemic metabolic keto-reduction of the prochiral carbonyl group of the oxcarbazepine molecule.