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.