**6. Mechanisms of idiosyncratic drug-induced neutropenia**

The pathogenesis of drug-induced neutropenia is a heterogeneous process, which is not yet fully understood [2, 3]. Clinical observations, studies in volunteers and laboratory experiments have suggested that this disorder is mediated by immune allergic and toxic mechanisms. In many cases, neutropenia occurs after prolonged drug exposure, resulting in decreased granulocyte production by hypoplastic bone marrow. In other cases repeated, intermittent exposure is implicated. This suggests an immune mediated mechanism, although this hypothesis is not entirely confirmed.

Direct damage, either to the microenvironment of the bone marrow or myeloid precursors, plays a significant role in most other cases [3]. Complex metabolic pathways that metabolize drugs and other chemicals are regulated by genetic factors. Genetic polymorphism results in heterogeneity of expression of the various enzymes, which generate or destroy intermediate toxic compounds [3].

Other mechanisms, involving cytotoxic T cells, haptens, auto-immunity, and oxidative modification of the drug have also been considered [3]. The impact of myeloperoxidase and NADPH-oxidase polymorphism in drug-induced neutropenia and agranulocytosis have also been studied. Clozapine appears to accelerate the process of apoptosis, thought to be due to depletion of ATP and reduced glutathione, which renders the neutrophils highly susceptible to oxidant-induced apoptosis [3].
