Comparative oxidation of loxapine and clozapine by human neutrophils

Abstract

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.

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

“…5d) and JL13, two oxygen isosteres, and also the thiazepine analogue clothiapine is slightly affected in oxidative conditions. This fact is in agreement with our previous data obtained in different experimental procedures for testing oxidative potential [4,5] and reports by other teams [6,29]. The oxidative effect of HRP/H 2 O 2 mixture on binding interaction can be prevented by addition of ascorbic acid to the incubation medium.…”

Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase®

“…The possible dosedependent effect on the adjusted reporting of haematologic malignancies in our study is consistent with the in vitro dosedependent toxicity of the clozapine-formed nitrenium ion (Gardner, Zahid, MacCrimmon, & Uetrecht, 1998;Pereira & Dean, 2006) and would reinforce the hypothesis of a clozapine-induced adverse effect. Bioactivation of clozapine in a nitrenium ion by the myeloperoxidase-hydrogen peroxide system of the activated neutrophils (Jegouzo et al, 1999;Uetrecht et al, 1997) and the cytochrome P450 (CYP) is the initial step in the haematological toxicity of both clozapine and olanzapine (Gardner et al, 1998;Sikora, Adamus, & Marcinek, 2007;Williams, Pirmohamed, Naisbitt, Uetrecht, & Park, 2000). Myeloperoxidase is expressed early in myeloid precursors in the bone marrow (Koeffler, Ranyard, & Pertcheck, 1985), and bone marrow stroma highly express various CYP, among which CYP3A4 appears to be the most important (Alonso et al, 2015).…”

“…Bioactivation of clozapine in a nitrenium ion by the myeloperoxidase-hydrogen peroxide system of the activated neutrophils (Jegouzo et al, 1999; Uetrecht et al, 1997) and the cytochrome P450 (CYP) is the initial step in the haematological toxicity of both clozapine and olanzapine (Gardner et al, 1998; Sikora, Adamus, & Marcinek, 2007; Williams, Pirmohamed, Naisbitt, Uetrecht, & Park, 2000). Myeloperoxidase is expressed early in myeloid precursors in the bone marrow (Koeffler, Ranyard, & Pertcheck, 1985), and bone marrow stroma highly express various CYP, among which CYP3A4 appears to be the most important (Alonso et al, 2015).…”

“…Indeed, despite very similar chemical structures, only clozapine and olanzapine possess nitrogen at position 5. The presence of sulphur (quetiapine) or oxygen (loxapine) at this latter position precludes the formation of a nitrenium ion (Jegouzo et al, 1999; Williams et al, 2000). Although both clozapine and olanzapine have the ability to form a nitrenium ion, it has been shown that the nitrenium ion formed from clozapine was more toxic at an equimolar dose than the nitrenium ion formed from olanzapine (Gardner et al, 1998; Ng, Kennar, & Uetrecht, 2014).…”

“…Also, a study performed with the Expanded Rochester Epidemiologic Project on approximately 1.8 million unique individual patients in 27 counties of Minnesota with data on clozapine prescription information (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) and data on diagnosis (2010)(2011)(2012)(2013)(2014)(2015) identified four cases of patients who developed lymphoma following clozapine exposure (Leung et al, 2018). Clozapine induced agranulocytosis is caused by the bioactivation of clozapine in an N-arylnitrenium ion (Jegouzo et al, 1999;Uetrecht, Zahid, Tehim, Mim Fu, & Rakhit, 1997). N-Arylnitrenium ions are recognised as active reactive intermediates in chemical carcinogenesis (Novak & Zhang, 2012).…”