The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.
Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.
Molyneux
Gemma
G
Division of Cellular and Molecular Medicine, Section for Cellular and Molecular Pathology, St. George's, University of London, London,UK.
Gibson
Frances M
FM
Chen
Christabelle M
CM
Marway
Harpal K
HK
McKeag
Sean
S
Mifsud
Charles V J
CV
Pilling
Andrew M
AM
Whayman
Matthew J
MJ
Turton
John A
JA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001379:Azathioprine / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D010198:Pancytopenia / Q000139:chemically induced*
D007166:Immunosuppressive Agents; D001379:Azathioprine