A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes.
Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermediate at m/z 311. This is 2 mass units less than the protonated molecular ion of parent olanzapine and suggests that the reactive intermediate is a nitrenium ion. The reactive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we reported previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabolites showed differences in their ability to cause toxicity to human neutrophils. Toxicity to neutrophils was observed only at high concentrations of clozapine (>50 microM) when HOCl was used to generate reactive metabolite. In contrast, concentration-dependent toxicity (p < 0.05) was observed when neutrophils were incubated with clozapine (0-20 microM) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of > 50 microM). Similar results were observed in monocytes and HL-60 cells. Olanzapine reactive metabolite only seemed to cause slight toxicity at the highest concentrations tested (20 microM), even when the reactive metabolite was generated using H2O2. Neutrophils from two patients with a history of clozapine-induced agranulocytosis seemed to be more sensitive to the toxic effects of the clozapine reactive metabolite; however, the numbers are too small to draw any definite conclusions.
Gardner
I
I
Faculties of Pharmacy, University of Toronto, Ontario, Canada.
Zahid
N
N
MacCrimmon
D
D
Uetrecht
J P
JP
D000380:Agranulocytosis / Q000139:chemically induced; D014150:Antipsychotic Agents / Q000378:metabolism*; D001569:Benzodiazepines; D003024:Clozapine / Q000378:metabolism* / Q000633:toxicity; D018922:HL-60 Cells; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D000077152:Olanzapine; D010084:Oxidation-Reduction; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D010890:Pirenzepine; D006997:Hypochlorous Acid; D003024:Clozapine; D000077152:Olanzapine