Patterns of Azathioprine Metabolites in Neutrophils, Lymphocytes, Reticulocytes, and Erythrocytes

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Abstract
Monitoring of azathioprine (AZA) therapy by the measurement of 6-thioguanine nucleotides (6-TGN) concentrations in red blood cells (RBC) may improve safety and ensure optimal immunosuppressive effects of AZA in organ transplantation. The authors explored the rationale for such monitoring by measuring thiopurine metabolites in peripheral blood cell types that are more relevant to the effects and kinetics of AZA and its active metabolites. Neutrophil granulocytes were isolated by density gradient centrifugation, and CD4+ lymphocytes and reticulocytes by using specific immunomagnetic beads. In neutrophils, 6-TGN concentrations had median measurements 31 times higher than in RBCs. In contrast to the high methylated mercaptopurine (me-MP) concentrations in RBCs, these metabolites were not detected in the neutrophils. Thiopurine metabolite levels were lower than the analytic limit of detection in all the CD4+ samples. The concentrations of 6-TGN and me-MPs were lower in reticulocytes than in RBCs in general, indicating that thiopurine metabolites are taken up by RBCs in the circulation. This study's findings, that 6-TGN concentrations are very high in neutrophils, whereas me-MPs are undetectable, may explain the specific neutropenic adverse effect of AZA. The results also add support to monitoring AZA through measurements of 6-TGN and me-MPs in RBCs.

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