Value of in vitro models for the assessment of drug-induced haematotoxicity.
BACKGROUND
A new antipsychotic compound induced unexpected red cell hypoplasia (reticulocytopenia, red marrow hypoplasia) in rats dosed orally for 7 days.


METHODS
Since 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 2 days (rat) or 7 days (human) and CFU-GM was cultured for 7 days (rat) or 10 days (human).


RESULTS
The drug induced inhibition of erythroid progenitors and myeloid progenitors for both species from 3 x 10(-5) mol/L, with the concentration inhibiting the growth of 50% (IC50) consistent with drug plasma levels measured in rats.


CONCLUSIONS
These 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.
Goldfain-Blanc
Françoise
F
Drug Safety Assessment, Biologie Servier, Gidy, France.
Wattrelos
Olivier
O
Casadevall
Nicole
N
Beamonte
Anne
A
Delongeas
Jean-Luc
JL
Claude
Nancy
N
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001854:Bone Marrow Cells / Q000502:physiology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004921:Erythropoietin / Q000502:physiology; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000175:diagnosis*; D006801:Humans; D008954:Models, Biological; D051381:Rats; D018570:Risk Assessment; D013234:Stem Cells / Q000502:physiology
D014150:Antipsychotic Agents; D004921:Erythropoietin