The metabolism of ¹⁴C-oxcarbazepine in man

Abstract

1. The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of ¹⁴C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects.

2. In the 0–6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47 779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary ¹⁴C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (∼4%), and a phenolic derivative of GP 47 779 (<1%).

3. The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47 779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47 779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.