Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemic mixture to dogs

Andrew Volosov, Boris Yagen, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Purpose: 10-hydroxycarbazepine (MHD) is the active metabolite of the new antiepileptic drug oxcarbazepine. MHD is a chiral molecule with an asymmetric carbon at position 10. The purpose of this study was to evaluate the stereo-selectivity in the pharmacokinetics of the enantiomers of MHD after oral administration of the individual MHD enantiomers and the racemic mixture to dogs. Methods: A racemic mixture of MHD and the individual MHD enantiomers were administered to six dogs in a crossover design. Plasma and urine concentrations of R(-)- and S(+)-MHD were determined by a stereoselective high-performance liquid chromatography assay. Results: The area under the concentration-time curve of R(-)-MHD was significantly greater than that of S(+)-MHD after the administration of the individual enantiomers but not after the administration of MHD in a racemic form. The formation clearance of the S(+)-MHD glucuronide was approximately three times greater than that of R(-)-MHD glucuronide. No difference was found in the renal clearance and protein binding of R(-)- and S(+)-MHD enantiomers. Conclusions: The pharmacokinetics of the MHD enantiomers was found to be stereoselective, mainly as a result of the stereoselectivity in the glucuronidation process. The difference in the pharmacokinetic parameters found after administration of individual MHD enantiomers compared with the administration of MHD in a racemic form suggests the possibility of interaction between the two enantiomers. Stereoselective pharmacokinetic and pharmacodynamic studies are needed to evaluate the rationale of developing MHD as a new antiepileptic drug, either in a stereospecific or racemic form.

Original languageEnglish
Pages (from-to)1107-1111
Number of pages5
JournalEpilepsia
Volume41
Issue number9
DOIs
StatePublished - 2000

Keywords

  • 10-Hydroxycarbazepine
  • Glucuronidation
  • Oxycarbazepine
  • Stereoselective pharmacokinetic analysis

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