Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects

• Published in: Clinical pharmacology and therapeutics 1999-12, Vol.66 (6), p.547-553
• Main Authors: Volosov, Andrew, Xiaodong, Sun, Perucca, Emilio, Yagen, Boris, Sintov, Amnon, Bialer, Meir
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1053/cp.1999.v66.103170001

Background and Objectives Oxcarbazepine is a new antiepileptic drug which in humans acts as a prodrug to its central nervous system–active metabolite 10‐hydroxycarbazepine. Because 10‐hydroxycarbazepine is a chiral molecule, the objective of the study was to perform a stereoselective pharmacokinetic analysis of 10‐hydroxycarbazepine in humans. Methods The pharmacokinetics and disposition of the enantiomers of 10‐hydroxycarbazepine were investigated in 12 healthy Chinese subjects. Each subject received a single oral dose of 600 mg oxcarbazepine and the concentrations of R‐ and S‐10‐hydroxycarbazepine in serum were determined by a stereoselective HPLC assay. The enantiomers of free and conjugated 10‐hydroxycarbazepine and of the oxidized diol metabolite were also quantified in urine. Results At all sampling times, the serum concentrations of S‐10‐hydroxycarbazepine were much higher than those of R‐10‐hydroxycarbazepine, and their ratio also tended to increase with time. The area under the serum concentration versus time curve of S‐10‐hydroxycarbazepine was about fivefold greater than that of R‐10‐hydroxycarbazepine (129.8 ± 33.1 versus 26.3 ± 8.5 mg/L · h; P < .001). Half‐lives did not differ significantly between the enantiomers (11.9 ± 3.3 hours for R‐10‐hydroxycarbazepine versus 13.0 ± 4.1 hours for S‐10‐hydroxycarbazepine). About 27% of the molar dose of oxcarbazepine was recovered in urine, mostly as the S‐enantiomer of 10‐hydroxycarbazepine and its conjugates. Carbamazepine‐10,11‐trans‐dihydrodiol accounted for less than 3% of urinary metabolites. Conclusions The marked differences in serum levels and urinary excretion between the two enantiomers of 10‐hydroxycarbazepine are likely to be related primarily to stereoselective presystemic metabolic keto‐reduction of the prochiral carbonyl group of the oxcarbazepine molecule. Clinical Pharmacology & Therapeutics (1999) 66, 547–553; doi: 10.1053/cp.1999.v66.103170001