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

Purpose: 10-hydroxycarbazepine (MHD) is the active metabolite of the new an tiepileptic drug oxcarbazepine. MHD is a chiral molecule with an asymmetric carbon at position 10. The purpose of this study was to evaluate the stere oselectivity in the pharmacokinetics of the enantiomers of MHD after oral a dministration of the individual MHD enantiomers and the racemic mixture to dogs. Methods: A racemic mixture of MHD and the individual MHD enantiomers were a dministered to six dogs in a crossover design. Plasma and urine concentrati ons of R(-)- and S(+)-MHD were determined by a stereoselective high-perform ance liquid chromatography assay. Results: The area under the concentration-time curve of R(-)-MHD was signif icantly greater than that of S(+)-MHD after the administration of the indiv idual enantiomers but not after the administration of MHD in a racemic form . The formation clearance of the S(+)-MHD glucuronide was approximately thr ee times greater than that of R(-)-MHD glucuronide. No difference was found in the renal clearance and protein binding of R(-)- and S(+)-MHD enantiome rs. Conclusions: The pharmacokinetics of the MI-ID enantiomers was found to be stereoselective, mainly as a result of the stereoselectivity in the glucuro nidation process. The difference in the pharmacokinetic parameters found af ter administration of individual MHD enantiomers compared with the administ ration of MI-ID in a racemic form suggests the possibility of interaction b etween the two enantiomers. Stereoselective pharmacokinetic and pharmacodyn amic studies are needed to evaluate the rationale of developing MHD as a ne w antiepileptic drug, either in a stereospecific or racemic form.