S. Gravel,1 J. Huguet,1 F. Gaudette,2 J. Turgeon,1 V. Michaud1; 1CRCHUM/Université de Montréal, Montreal, QC, Canada, 2CRCHUM, Montreal, QC, Canada

BACKGROUND: Many second-generation antipsychotics, such as iloperidone (ILO), can block hERG potassium channels leading to an increased risk of QT prolongation and Torsades de pointes. In the liver, ILO undergoes extensive metabolism by demethylation (CYP3A4), hydroxylation (CYP2D6) and reduction (microsomal and cytosolic enzymes). We have previously demonstrated that CYP450s expressed in the human heart exhibit drug-metabolism activities which could affect intracellular drug concentration and predispose to cardiac adverse events. Our objective was to evaluate the metabolism of ILO in human heart tissue.
METHODS: Human heart specimens were obtained from left ventricles (n=3) and microsomal and cytosolic fractions were prepared using a differential centrifugation technique. Incubations were performed with ILO (200 µM) in both matrices. ILO and its metabolites (reduced ILO=P88, O-demethyl ILO=M413 and OH-ILO =M443 and Carboxyl-ILO=P95) were quantified by LC-MS/MS.
RESULTS: Our results showed that ILO was metabolized in heart tissue and two major metabolites were produced: P88 and M413. The greatest activity was observed for the formation of P88 in the cytosolic fractions (8.53 2.20 pmol/min/mg prot) compared to microsomal fraction (2.57 1.39 pmol/min/mg prot). Formation of the M413 was only observed in microsomal fractions (1.36 ± 0.73 pmol/min/mg prot). P95 and M443 were not detected in the heart fractions.
CONCLUSION: Our results demonstrated that ILO was metabolized by human heart from both cytosolic and microsomal fractions. The P88 metabolite has been associated with hERG block. Our data indicate that local metabolism in the heart could modulate intracellular concentrations of ILO and predispose to QT prolongation.