Stereoselective pharmacokinetic analysis of the antiepileptic 10-hydroxycarbazepine in dogs

The active entity of the new antiepileptic drug, oxcarbazepine (OXC), is 10 -hydroxycarbazepine (MHD). In humans, OXC undergoes rapid presystemic (firs t-pass) metabolic reduction to MHD. MHD is a chiral molecule with an asymme tric carbon at position 10. Previous reports have shown that in humans, the first-pass metabolic reduction of OXC into MHD is stereoselective, resulti ng in a 1-to-4 AUC ratio of R(-) and S(+) enantiomers. The objective of the current study was to investigate whether the pharmacokinetics of MHD was s tereoselective. Racemic MHD was thus administered intravenously (IV) and or ally to six dogs, and plasma samples were analyzed by a stereospecific, hig h-performance liquid chromatographic (HPLC) assay. We found that R(-)-MHD h ad a clearance similar to that of S(+)-MHD; however, a difference was found between the volume of distribution (V-d) and consequently, between the hal f-lives of the two MHD enantiomers. The main pharmacokinetic parameters of R(-)- and S(+)-MHD were as follows: A terminal half-life (t(1/2)) of 2.2 +/ - 0.4 hours for R(-)-MHD and of 3.8 +/- 0.3 hours for S(+)-MHD; a clearance (CL) of 7.8 +/- 1.3 L/h for R(-)-MHD and of 8.6 +/- 2.1 L/h for S(+)-MHD; a V-d of 25 +/- 6 L for ,R(-)-MHD and of 47 +/- 14 L for S(+)-MHD; and a V- d at steady state (V-ss) of 22.8 +/- 3.6 for R(-)-MHD and of 29.9 +/- 4.1 f or S(+)-MHD. After its oral administration to dogs, the absolute bioavailab ility was 78.4 +/- 20.9% for R(-)-MHD and 78.5 +/- 27.3% for S(+)-MHD; t(1/ 2) was 2.7 +/- 0.6 hours for R(-)-MHD and 4.1 +/- 0.8 hours for S(+)-MHD. T hese results showed stereoselectivity in the volume of distribution and con sequently, the t(1/2) of S(+)-MHD was longer than that of R(-)-MHD after bo th TV and oral administration to dogs.