Comparative oxidation of loxapine and clozapine by human neutrophils

The clozapine-induced agranulocytosis could be due to the formation of a re active intermediate formed in polymorphonuclear neutrophils and granulocyte precursors with the myeloperoxidase-hydrogen peroxide system. On the contr ary, no case of agranulocytosis has been described for loxapine, an other n euroleptic drug with a Very close structural analogy. We have compared the clozapine and loxapine interaction with the oxidative burst and particularl y with this enzymatic complex. On the one hand, the assay of the oxidative species demonstrated a different impact for the two neuroleptics. The 50% i nhibitory concentration was 92 mu M for hydrogen peroxide and 40 mu M for h ypochlorous acid for loxapine. The loxapine target is located before the my eloperoxidase-hydrogen peroxide system in the oxidative stream, whereas clo zapine diverts the chlorination pathway of the enzyme. On the other hand, t he in vitro metabolism of drugs by the myeloperoxidase-hydrogen peroxide sy stem has been investigated by mass spectrometry. Loxapine remains inert but clozapine undergoes the oxidation. The glutathione or ascorbate addition i n the medium leads to a removal of the oxidation. Glutathione is able to tr ap the toxic intermediate and could avoid its formation. (C) Elsevier, Pari s.