The metabolism of¹⁴C-oxcarbazepine in man

Abstract

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. 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 (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). 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.

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

“…Because the metabolism of OXC or MHD barely uses catalytic oxidation by CYP450 (only approximately 4% of MHD is oxidized to the inactive dihydroxy derivative), there is only a small potential for the metabolism of OXC or MHD to be affected by the inducers of CYP [2,5,16] . However, some studies suggest that the classical enzyme-inducing AEDs such as CBZ, PB and PHT may increase the metabolism of MHD.…”

“…Based on previous research [2,5,15,16] , we first proposed the following assumptions： OXC was completely absorbed (the bioavailability was fixed at 1.0) and metabolized to the same amount of MHD in the mass unit. The first-order conditional estimation method with the η-ε interaction option (FOCE L-B) was used throughout the model building process.…”

Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

“…In humans, formation of MHD is stereoselective, with the two enantiomers formed in a ratio of 80% (S enantiomer of MHD [(S)-MHD]) to 20% (R enantiomer of MHD [(R)-MHD]) (Flesch et al, 1992). After oral administration of radiolabeled OXC, only 2% of total radioactivity in plasma is due to unchanged OXC, and approximately 70% is due to MHD (Schütz et al, 1986). Minor amounts of oxcarbazepine are transformed in a sulfate conjugate and directly conjugated (Schütz et al, 1986).…”

“…Oxcarbazepine is rapidly reduced by cytosolic arylketone reductases to the monohydroxy derivative (MHD) (Fig. 1) (Schütz et al, 1986;Menge and Dubois, 1983). In humans, formation of MHD is stereoselective, with the two enantiomers formed in a ratio of 80% (S enantiomer of MHD [(S)-MHD]) to 20% (R enantiomer of MHD [(R)-MHD]) (Flesch et al, 1992).…”

A Structurally Diverse Heterocyclic Library by Decoration of Oxcarbazepine Scaffold

“…Although the precise mechanism by which OXC exerts its antiseizure effect is unknown, it is well documented that OXC is completely adsorbed and extensively metabolized (approximately 70%) by reductase enzymes to its pharmacologically active 10-monohydroxy derivative form eslicarbazepine ((S)-licarbazepine, MHD, Figure 1) [5]. The structure-activity relationships to date have shown that the potency and selectivity of 1 are linked to the N-carboxamido group embodied in the twisted boat conformation of the dibenzoazepine core [6].…”