Optimisation of azathioprine immunosuppression after organ transplantation by pharmacological measurements.

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 x 10(8) 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 x 10(8) 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.