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A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes.

Abstract：

: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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Gardner I,Zahid N,MacCrimmon D,Uetrecht JP

subject

Has Abstract

pub_date

1998-06-01 00:00:00

pages

991-8

issue

6

eissn

0026-895X

issn

1521-0111

journal_volume

53

pub_type

杂志文章

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