Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects

Clin Pharmacol Ther. 1999 Dec;66(6):547-53. doi: 10.1053/cp.1999.v66.103170001.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anticonvulsants / administration & dosage*
  • Anticonvulsants / blood
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / urine
  • Asian People
  • Carbamazepine / administration & dosage
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood
  • Carbamazepine / chemistry
  • Carbamazepine / pharmacokinetics
  • Carbamazepine / urine
  • China
  • Chromatography, High Pressure Liquid
  • Female
  • Humans
  • Male
  • Middle Aged
  • Oxcarbazepine
  • Reference Values
  • Stereoisomerism

Substances

  • 10,11-dihydro-10-hydroxycarbamazepine
  • Anticonvulsants
  • Carbamazepine
  • Oxcarbazepine