BIOACTIVATION OF CARBAMAZEPINE IN THE RAT IN-VIVO - EVIDENCE FOR THE FORMATION OF REACTIVE ARENE OXIDE(S)

The metabolism of carbamazepine (CBZ) and its major metabolite in huma ns, carbamazepine 10,11-epoxide (CBZ-E), was examined in the rat in vi vo. Particular emphasis was placed on the identification of dihydrohyd roxythio adducts, which are detoxication products of reactive arene ox ide intermediates. Anesthetized and cannulated male Wistar rats were a dministered [H-3]CBZ (25 mu g . kg(-1) or 25 mg . kg(-1)) or [H-3]CBZ- E (25 mu g . kg(-1) or 25 mg . kg(-1)) intravenously and bile and urin e collected for 5 hr. Less than 8% of drug was excreted in the urine f or each dosing regimen. Biliary excretion accounted for 73.7 +/- 6.2 a nd 41.8 +/- 6.2% (mean +/- SD, N = 4) of administered CBZ (25 mu g . k g(-1) and 25 mg . kg(-1) respectively) and 47.6 (N = 2) and 28.1 +/- 6 .0% of administered CBZ-E (25 mu g . kg(-1) and 25 mg . kg(-1), respec tively). The major route of metabolism of both CBZ and CBZ-E was N-glu curonidation. 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 lo wer dose of 25 mu g . 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 mg . kg(-1)), the N-glucuronide of the parent compound was the maj or metabolite, accounting for 19.1 +/- 4.5% of the dose. O-glucuronide s 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 isomeric glutathionyl dihydrohydroxy-CBZ adducts were identified by LC /MS. They collectively accounted for 5.8 +/- 0.9% of the dose. In conc lusion, we have provided evidence, in rats, for the generation of a re active arene oxide species from CBZ. If not adequately detoxified, via conjugation with glutathione, this has the potential to initiate cell ular damage. In humans, a similar mechanism may be involved in CBZ-ass ociated hypersensitivity.