Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils

doi:10.1016/0006-2952(93)90279-6

Biochemical Pharmacology

Volume 45, Issue 6, 24 March 1993, Pages 1267-1275

https://doi.org/10.1016/0006-2952(93)90279-6 Get rights and content

Abstract

Carbamazepine is an anticonvulsant which is associated with a significant incidence of hypersensitivity reactions including agranulocytosis. We have postulated that many drug hypersensitivity reactions, especially agranulocytosis and lupus, are due to reactive metabolites generated by the myeloperoxidase (MPO) (EC 1.11.1.7) system of neutrophils and monocytes. This led to a study of the metabolism and covalent binding of carbamazepine with MPO/H₂O₂/Cl⁻ and neutrophils. Metabolism and covalent binding were observed in both systems and the same pathway appeared to be involved; however, the metabolism observed with the MPO system was approximately 500-fold greater than that observed with neutrophils. The metabolites identified were an intermediate aldehyde, 9-acridine carboxaldehyde, acridine, acridone, choloroacridone, and dichloroacridone. We postulate that the first intermediate in the metabolism of carbamazepine is a carbonium ion formed by reaction of hypochlorous acid (HOCl) with the 10,11 double bond. Although we have no direct proof for the proposed carbonium ion, it provides the most likely mechanism for the observed ring contraction. Iminostilbene, a known metabolite of carbamazepine, was also metabolized by a similar pathway leading to ring contraction; however, the rate was much faster and the first step may involve N-chlorination and a nitrenium ion intermediate. These data confirm that carbamazepine is metabolized to reactive intermediates by activated leukocytes. Such metabolites could be responsible for some of the adverse reactions associated with carbamazepine, especially reactions such as agranulocytosis and lupus which involve leukocytes.

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^☆: A preliminary report of this work was presented at the Third North American Meeting of the International Society for the Study of Xenobiotics, San Diego, CA.

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Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils☆

Abstract

J Pharm Sci

J Pharm Sci

J Biol Chem

Results of a Nationwide Veterans Administration Cooperative study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin and primidone

Epilepsia

A case of drug induced lupus due to carbamazepine

J Rheumatol

Drug-induced agranulocytosis

Drugs

Fatal aplastic anemia in a patient treated with carbamazepine