In vitro and animal models of drug-induced blood dyscrasias

Abstract

Drug-induced blood dyscrasias can be either acute and predictable or delayed and unpredictable (idiosyncratic). The predictable toxicity is relatively easy to reproduce with in vitro models, although they may not work for drugs that require bioactivation. It is very unlikely that idiosyncratic blood dyscrasias can be modeled in vitro, although some drugs (or their reactive metabolites) that cause idiosyncratic reaction are toxic to bone marrow cells in vitro. Although the mechanisms of idiosyncratic reactions are poorly understood, there is evidence that most are due to reactive metabolites and some are immune-mediated. Therefore screening drugs for their bioactivation by myeloperoxidase, the major oxidative enzyme in bone marrow, may provide some measure of the risk that a drug will cause blood dyscrasias. Several examples of drug-induced idiosyncratic agranulocytosis, aplastic anemia and thrombocytopenia are presented, but better in vivo models are clearly needed to gain a clearer understanding of these adverse reactions.