Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemicmixture to dogs
A. Volosov et al., Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemicmixture to dogs, EPILEPSIA, 41(9), 2000, pp. 1107-1111
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.