Value of In Vitro Models for the Assessment of Drug-Induced Haematotoxicity

Abstract

BackgroundA new antipsychotic compound induced unexpected red cell hypoplasia (reticulocytopenia, red marrow hypoplasia) in rats dosed orally for 7days. Materials and methodsSince an erythropoietin-mediated pathogenesis was excluded, in vitro tests on rat and human bone marrow cells were performed with measurement of formation of late erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) colony-forming units after incubation with the drug. CFU-E together with growth factors were cultured for 2days (rat) or 7days (human) and CFU-GM was cultured for 7days (rat) or 10days (human). ResultsThe drug induced inhibition of erythroid progenitors and myeloid progenitors for both species from 3×10−5 mol/L, with the concentration inhibiting the growth of 50% (IC50) consistent with drug plasma levels measured in rats. ConclusionThese cloning assays on rat bone-marrow cells were shown to be adequate models for determining the haematotoxicity of the agent and to be predictive of human toxicity. With only a small amount of compound required, they can be used as screening tools to detect haematotoxic potential of candidate drugs.