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Optimisation of Azathioprine Immunosuppression After Organ Transplantation by Pharmacological Measurements

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Summary

Azathioprine undergoes extensive metabolism in vivo. Most of its immunosuppressive and myelotoxic effects are exerted by the intracellular metabolites 6-thioguanine nucleotides (6-TGN). There is large individual variability in thiopurine pharmacokinetics. When transplant recipients are started on the standard azathioprine dosage, low and probably subtherapeutic 6-TGN concentrations [<100 pmol/8 × 108 red blood cells (RBC)] are measured in the majority of patients with normal kidney function. When renal function is severely impaired, 6-TGN concentrations rise 8- to 10-fold or higher. Due to genetic polymorphism, the activity of the enzyme thiopurine methyltransferase (TPMT) is intermediate to undetectable in approximately 11 % of the population. With low TPMT activity, transmethylation is reduced and more intermediate metabolites are left for alternative pathways such as 6-TGN formation. High 6-TGN concentrations are associated with increased frequency and severity of leucopenia. It has been suggested that active monitoring of azathioprine to keep 6-TGN concentrations between 100 and 200 pmol/8 × 108 RBC may contribute to more effective treatment by reducing the incidence of rejection episodes and leucopenia. Such monitoring is currently being evaluated in a controlled, prospective study of renal allograft recipients.

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  1. Institute of Clinical Biochemistry and Department of Clinical Pharmacology, National Hospital, University of Oslo, Norway

    Stein Bergan

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Correspondence to Stein Bergan.

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Bergan, S. Optimisation of Azathioprine Immunosuppression After Organ Transplantation by Pharmacological Measurements. BioDrugs 8, 446–456 (1997). https://doi.org/10.2165/00063030-199708060-00005

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