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.