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Abstract
Carbamazepine is an anticonvulsant which associated with a significant incidence of idiosyncratic reactions including agranulocytosis. We have postulated that carbamazepine-induced idiosyncratic reactions are due to reactive metabolites generated by the myeloperoxidase enzyme system during the respiratory burst of activated leukocytes with HOCl as the main oxidizing agent. Studies done in order to test this hypothesis demonstrated carbamazepine was metabolized by neutrophils. Covalent binding of radiolabeled drug to neutrophils was also observed. We postulate the first intermediate in the metabolism of carbamazepine is a carbonium ion formed by reaction of HOCl with the 10,11 double bond. The major pathway involves ring contraction to 9-acridine carboxaldehyde. Although the metabolism of carbamazepine by neutrophils is slow relative to oxidation by HOCl, iminostilbene, a known liver metabolite of carbamazepine, is also metabolized by a similar pathway leading to ring contraction and the rate is much faster. Therefore, the degree to which carbamazepine is metabolized to iminostilbene could be a risk factor for carbamazepine-induced idiosyncratic reactions.
The covalent binding of 9-acridine carboxaldehyde to neutrophils was 100-fold that of carbamazepine which suggests the evidence that 9-acridine carboxaldehyde is the major metabolite responsible for binding to neutrophils.
Preliminary experiments were performed to test the biological effects of 9-acridine carboxaldehyde on leukocyte function in search of clues to the mechanism of carbamazepine-induced idiosyncratic reactions. Alteration of immune cell function by the reactive intermediate, 9-acridine carboxaldehyde was demonstrated by an increased proliferation at low concentrations and cytotoxicity at high concentrations.
An interesting observation made, using cells from patients who have a history of carbamazepine-induced adverse reactions, was an increased proliferative response of their cells in the autologous mixed lymphocyte reactions and lymphocyte transformation tests upon addition of indomethacin; however, this did not require the presence of drug or metabolite.
In short, carbamazepine was found to be metabolized by activated leukocytes to a chemically reactive metabolite which is toxic to lymphocytes and has effects on immune function; however, further studies with cells from patients with a clear history of carbamazepine-induced toxicity will be required to determine if this metabolite is responsible for toxicity, and if so, by what mechanism.
