A COMPARISON OF THE OXIDATION OF CLOZAPINE AND OLANZAPINE TO REACTIVEMETABOLITES 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 sp ectrometer 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 react ive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we rep orted previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabo lites showed differences in their ability to cause toxicity to human n eutrophils. Toxicity to neutrophils was observed only at high concentr ations of clozapine (>50 mu M) 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 mu M ) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of >50 mu M). Similar results were observed in monocytes and HL-60 cells. Olanzapine reacti ve metabolite only seemed to cause slight toxicity at the highest conc entrations tested (20 mu M), even when the reactive metabolite was gen erated using H2O2. Neutrophils from two patients with a history of clo zapine-induced agranulocytosis seemed to be more sensitive to the toxi c effects of the clozapine reactive metabolite; however, the numbers a re too small to draw any definite conclusions.