Stereoselective Pharmacokinetic Analysis of the Antiepileptic 10-Hydroxycarbazepine in Dogs

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Abstract

Summary:

The active entity of the new antiepileptic drug, oxcarbazepine (OXC), is 10-hydroxycarbazepine (MHD). In humans, OXC undergoes rapid presystemic (first-pass) metabolic reduction to MHD. MHD is a chiral molecule with an asymmetric carbon at position 10. Previous reports have shown that in humans, the first-pass metabolic reduction of OXC into MHD is stereoselective, resulting 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 stereoselective. Racemic MHD was thus administered intravenously (IV) and orally to six dogs, and plasma samples were analyzed by a stereospecific, high-performance liquid chromatographic (HPLC) assay. We found that R(-)-MHD had a clearance similar to that of S(+)-MHD; however, a difference was found between the volume of distribution (Vd) and consequently, between the half-lives of the two MHD enantiomers. The main pharmacokinetic parameters of R(-)- and S(+)-MHD were as follows: A terminal half-life (t½) 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 Vd of 25 ± 6 L for R(-)-MHD and of 47 ± 14 L for S(+)-MHD; and a Vd at steady state (Vss) of 22.8 ± 3.6 for R(-)-MHD and of 29.9 ± 4.1 for S(+)-MHD. After its oral administration to dogs, the absolute bioavailability was 78.4 ± 20.9% for R(-)-MHD and 78.5 ± 27.3% for S(+)-MHD; t½ was 2.7 ± 0.6 hours for R(-)-MHD and 4.1 ± 0.8 hours for S(+)-MHD. These results showed stereoselectivity in the volume of distribution and consequently, the t½ of S(+)-MHD was longer than that of R(-)-MHD after both IV and oral administration to dogs.

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