Bioactivation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide(s)

Abstract

The metabolism of carbamazepine (CBZ) and its major metabolite in humans, carbamazepine 10,11-epoxide (CBZ-E), was examined in the rat in vivo. Particular emphasis was placed on the identification of dihydrohydroxythio adducts, which are detoxication products of reactive arene oxide intermediates. Anesthetized and cannulated male Wistar rats were administered [3H]CBZ (25 micrograms.kg-1 or 25 mg.kg-1) or [3H]CBZ-E (25 micrograms.kg-1 or 25 mg.kg-1) intravenously and bile and urine collected for 5 hr. Less than 8% of drug was excreted in the urine for each dosing regimen. Biliary excretion accounted for 73.7 +/- 6.2 and 41.8 +/- 6.2% (mean +/- SD, N = 4) of administered CBZ (25 micrograms.kg-1 and 25 mg.kg-1, respectively) and 47.6 (N = 2) and 28.1 +/- 6.0% of administered CBZ-E (25 micrograms.kg-1 and 25 mg.kg-1, respectively). The major route of metabolism of both CBZ and CBZ-E was N-glucuronidation. In rats given CBZ (25 mg.kg-1), the N-glucuronide of the parent compound accounted for 12.6 +/- 2.6% of the dose, whereas CBZ-E N-glucuronide accounted for 12.3 +/- 3.8% of the dose. At the lower dose of 25 micrograms.kg-1, these accounted for 18.6 +/- 3.0 and 36.7 +/- 4.7% of the dose, respectively. Similarly, for rats given CBZ-E (25 micrograms.kg-1), the N-glucuronide of the parent compound was the major metabolite, accounting for 19.1 +/- 4.5% of the dose. O-glucuronides were relatively minor metabolites of both drugs. Glutathione adducts were identified in the bile of both groups of animals. Although these adducts were relatively minor metabolites of CBZ-E (1.8% of the dose), they were more substantial products of the metabolism of CBZ. Three isometric glutathionyl dihydrohydroxy-CBZ adducts were identified by LC/MS. They collectively accounted for 5.8 +/- 0.9% of the dose. In conclusion, we have provided evidence, in rats, for the generation of a reactive arene oxide species from CBZ. If not adequately detoxified, via conjugation with glutathione, this has the potential to initiate cellular damage. In humans, a similar mechanism may be involved in CBZ-associated hypersensitivity.