A. Volosov et al., Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects, CLIN PHARM, 66(6), 1999, pp. 547-553
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 pharmacokineti
c analysis of 10-hydroxycarbazepine in humans.
Methods: The pharmacokinetics and disposition of the enantiomers of 10-hydr
oxycarbazepine were investigated in 12 healthy Chinese subjects. Each subje
ct received a single oral dose of 600 mg oxcarbazepine and the concentratio
ns of R- and S-10-hydroxycarbazepine in serum were determined by a stereose
lective HPLC assay. The enantiomers of free and conjugated 10-hydroxycarbaz
epine and of the oxidized diol metabolite were also quantified in urine.
Results: At all sampling times, the serum concentrations of S-10-hydroxycar
bazepine were much higher than those of R-10-hydroxycarbazepine, and their
ratio also tended to increase with time. The area under the serum concentra
tion versus time curve of S-10-hydroxycarbazepine was about fivefold greate
r than that of R-10-hydroxycarbazepine (129.8 +/- 33.1 versus 26.3 +/- 8.5
mg/L h; P < .001), Half-lives did not differ significantly between the enan
tiomers (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 oxcarba
zepine was recovered in urine, mostly as the S-enantiomer of 10-hydroxycarb
azepine 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 b
etween the two enantiomers of 10-hydroxycarbazepine are likely to be relate
d primarily to stereoselective presystemic metabolic keto-reduction of the
prochiral carbonyl group of the oxcarbazepine molecule.