Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: Application to antipsychotic drugs

Some antipsychotic agents have been found to produce agranulocytosis and ap lastic anemia. The oxidation phenomena and/or the formation of free radical s has been suggested to be causally related to various hematological disord ers, e.g., agranulocytosis, Using five experimental conditions, we tested t he oxidative potential of compounds with and without a history of hematolog ical side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and wit hout a history of causing hematologic problems (<70%). The lipid peroxidati on system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtain ed when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4, A multivariate analysis taking into account the five variabl es provided 87.5% success in classification, The two clusters were better d iscriminated in terms of a "distance coefficient." In a second analysis, th e putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, an d JL25) were classified in the cluster of toxic compounds, while the oxa- a nd thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic co mpounds, On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herei n is, to our knowledge, the first which classifies molecules of different s tructures as well. as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-indu ced hematological side effects. (C) 1999 Academic Press.