Comparative oxidation of loxapine and clozapine by human neutrophils

The clozapine-induced agranulocytosis could be due to the formation of a reactive intermediate formed in polymorphonuclear neutrophils and granulocyte precursors with the myeloperoxidase-hydrogen peroxide system. On the contrary, no case of agranulocytosis has been described for loxapine, an other neuroleptic drug with a very close structural analogy. We have compared the clozapine and loxapine interaction with the oxidative burst and particularly with this enzymatic complex. On the one hand, the assay of the oxidative species demonstrated a different impact for the two neuroleptics. The 50% inhibitory concentration was 92 microM for hydrogen peroxide and 40 microM for hypochlorous acid for loxapine. The loxapine target is located before the myeloperoxidase-hydrogen peroxide system in the oxidative stream, whereas clozapine diverts the chlorination pathway of the enzyme. On the other hand, the in vitro metabolism of drugs by the myeloperoxidase-hydrogen peroxide system has been investigated by mass spectrometry. Loxapine remains inert but clozapine undergoes the oxidation. The glutathione or ascorbate addition in the medium leads to a removal of the oxidation. Glutathione is able to trap the toxic intermediate and could avoid its formation.