Metabolism of Clozapine† by Neutrophils

Abstract

Many types of adverse drug reactions appear to involve reactive metabolites which, by their very nature, usually have short biological half-lives. Therefore, reactive metabolites formed by neutrophils, or neutrophil precursors in the bone marrow, would seem more likely to be responsible for drug-induced agranulocytosis than metabolites formed in the liver. We have found that several drugs associated with a relatively high incidence of drug-induced agranulocytosis are metabolised by activated neutrophils to chemically reactive metabolites. In preliminary experiments with clozapine, we found that clozapine was metabolised by neutrophils. It also reacted with hypochlorous acid, the principal oxidant generated by neutrophils, to form a reactive intermediate. This intermediate has a half-life of I minute in buffer, but reacts very rapidly with glutathione. We believe that this intermediate is a nitrenium ion. Such a metabolite could be responsible for clozapine-induced agranulocytosis, either by direct toxicity or through an immunemediated mechanism.

Clozapine-induced agranulocytosis

“…They hypothesized that the toxicity of N-desmethylclozapine may be compounded by another metabolic intermediate, such as nitrenium ion. Uetrecht et al [32] found evidence that CZP is metabolized, by the action of myeloperoxidase, to a nitrenium ion, a short-lived but highly reactive metabolite. The pivotal role of myeloperoxidase in this metabolic step could explain why CZP and its metabolites affect almost exclusively granulocytes and their precursors.…”

Metabolism of clozapine by human neutrophils: evidence for a specific oxidation of clozapine by the myeloperoxidase system with inhibition of enzymatic chlorination cycle

“…This mechanism explains the inhibition of HOCl production by CLZ. The presumed mode of electron transfer is detailed in A current explanation for clozapine-induced agranulocytosis attributes pathogenesis to chemically reactive metabolites that are thought to act against neutrophils and/or their precursors either directly or via an immunological mechanism (Uetrecht, 1992). CLZ is metabolised to a reactive intermediate by the human hepatic P450 enzyme system (Pirmohamed et al, 1995), but the rapid detoxication allows protection of hepatocytes.…”

Toxicity

“…Clozapine exhibits covalent binding to human neutrophil proteins in vitro, via MPO-mediated oxidation of the dibenzodiazepine ring to a reactive iminium ion, which covalently binds to the target tissues and also reacts with GSH ( Figure 8.8) [32,33]. There are several instances of prototype drugs associated with toxicity that also form reactive metabolites and elimination of this liability in followon successor agent(s) markedly improves the safety profile.…”