Clozapine-associated perturbation of arachidonic acid metabolism: A future direction for clozapine-induced cardiotoxicity.

Clozapine is an effective antipsychotic medication utilised for treatment-resistant schizophrenia. However, clinical use of clozapine is limited due to the risk of cardiotoxicities, including clozapine-induced myocarditis. Oxidation of clozapine and reduction of clozapine-N-oxide can be catalysed by the cardio-selective cytochrome P450 (CYP) isoforms CYP2J2, CYP1A1 and CYP1B1, which are also reported to metabolise arachidonic acid. Any interaction with CYP-catalysed arachidonic acid metabolism may perturb the balance of pro-inflammatory hydroxyeicosatetraenoic acids and anti-inflammatory epoxyeicosatrienoic acids, priming the heart to an inflammatory state. Thereby making it more susceptible to the damage that may induce clozapine-induced myocarditis. The purpose of this preliminary study was to investigate whether an interaction between arachidonic acid and clozapine or clozapine-N-oxide occurs at CYP2J2, CYP1A1 and CYP1B1, in comparison to the hepatic isoform CYP2C19. Our results demonstrated a clear perturbation of CYP1B1 catalysed arachidonic acid metabolism, with a concentration-dependent decrease in metabolite formation in the presence of clozapine and clozapine-N-oxide. Each isoform also had decreased N-desmethylclozapine formation relative to incubations with clozapine alone and impaired clozapine and clozapine-N-oxide REDOX cycling capacity. Although limited by analytical sensitivity, these data provide clear evidence of a metabolic interaction between arachidonic acid and clozapine. This offers a novel hypothesis to explain patient susceptibility and a feasible mechanism for the cardiac-selective inflammation observed in clozapine-induced myocarditis.