Clozapine and its Major Stable Metabolites, N-desmethylclozapine and Clozapine N-oxide do not Affect Human Bone Marrow Stromal Cells in vitro

Abstract

Treatment of refractory schizophrenia with the atypical antipsychotic drug clozapine is associated with life-threatening agranulocytosis, characterised by a drop in neutrophil count. Theoretically, toxicity may be accounted for by direct action of parent drug or one of its stable metabolites on bone marrow stroma given importance of these cells to neutrophil maturation. Effects of clozapine, N-desmethylclozapine and clozapine N-oxide on stromal cell viability were therefore assessed using human primary long-term bone marrow culture and stromal cell lines, HAS303 and LP101, to define cell-specificity of response. Clozapine, N-desmethylclozapine and clozapine N-oxide had no significant effect on bone marrow stromal, HAS303 and LP101 viability over a wide drug concentration range (10-20000 ng mL 1 ) compared with cells in absence of drug. Hence it is unlikely that parent drug or its stable metabolites are directly toxic to stroma under clinical conditions. Reduced capability of stroma to support myelopoiesis, however, cannot be excluded.