Clozapine Cytotoxics

CLOZAPINE CYTOTOXICS t risk of bone marrow toxicity Additive effect Avoid co-administration... 

The heme iron in the peroxidase is oxidized by the peroxide from III+ to V4- in compound I. The compound I is reduced by two sequential one-electron transfer processes giving rise to the original enzyme. A substrate-free radical is in turn generated. This may have toxicological implications. Thus the myeloperoxidase in the bone marrow may catalyze the metabolic activation of phenol or other metabolites of benzene. This may underlie the toxicity of benzene to the bone marrow, which causes aplastic anemia (see below and chap. 6). The myeloperoxidase found in neutrophils and monocytes may be involved in the metabolism and activation of a number of drugs such as isoniazid, clozapine, procainamide, and hydralazine (see below). In in vitro systems, the products of the activation were found to be cytotoxic in vitro. 

Some explanations of the lower risk of agranulocytosis have been advanced after an in vitro cytotoxicity study (209). Like clozapine, olanzapine is oxidized to a reactive nitrenium ion by HOC1, the major oxidant produced in activated neutrophils. However, the olanzapine-reactive metabolite has a lower propensity to cause toxicity to human neutrophils, monocytes, and HL-60 cells than the reactive clozapine nitrenium ion. The lower toxic potential of the olanzapine reactive metabolite, in conjunction with the lower therapeutic plasma concentrations of olanzapine compared with clozapine, may help to explain this difference between the drugs. 

UK manufacturer lists carbamazepine (see also Clozapine + Anti epileptics , p.744), chloramphenicol, cytotoxics, penicillamine, pyrazolone analgesics (e.g. phenylbutazone), sulphonamides (e.g. co-trimoxazole) and, because they cannot be stopped if an adverse reaction occurs, they advise against the use of depot antipsychotics. There are several cases that confirm the clinical significance of these predicted interactions. 

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