Presence and ex vivo formation of acridone in blood of patients routinely treated with carbamazepine: exploration of the 9-acridinecarboxaldehyde pathway

Abstract

Carbamazepine (CBZ) is a useful anticonvulsive drug associated with rare severe adverse drug reactions. The physio-pathological mechanisms of these reactions are unknown although evidence of immunological activation has been reported. The ability of 9-acridinecarboxaldehyde, a CBZ metabolite, to interact with leukocyte constituents was demonstrated, and catabolism of this compound into acridine (AI) and acridone (AO) was observed in vitro.In this study, we have assessed ex vivo the role of the extra-hepatic 9-acridinecarboxaldehyde pathway in the metabolism of CBZ. First, we verified the presence of the terminal metabolites AI and AO in CBZ-treated patients. Then, we tested ex vivo the transformation of CBZ, epoxy CBZ, iminostilbene, and AI into AO in the blood of these patients.We observed no direct formation of hydroxylated CBZ metabolites in isolated blood, and CBZ did not react with blood cells. Conversely, we detected a dose-dependent transformation of epoxy CBZ, iminostilbene, and AI into AO with individual variations from patient to patient.AO might thus be considered as a metabolite of 9-acridinecarboxaldehyde that does not react with cells (detoxicant pathway) as well as a marker of the formation of toxic AI derivatives (toxicant pathway).