6-mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype

Prevention of allograft transplant rejection by the immunosuppressive 6-thi opurine drug azathioprine is limited by haematological toxicity (leucopenia or agranulocytosis). This toxicity is particularly apparent in subjects wi th low thiopurine methyltransferase activity (TPMTase) phenotype (1% in the Caucasian population). The thiopurine derivative 6-mercaptopurine is the a ctive metabolite of azathioprine, and it would be of interest to measure, a fter validation of plasma measurements, the mean values of the pharmacokine tic parameters in transplant patients with high or intermediate TPMTase phe notypes (85 and 14% of the Caucasian population, respectively). We measured erythrocyte TPMTase activity in 103 kidney transplant recipient s of high or intermediate phenotype and calculated, after a test dose of az athioprine, the mean values of the pharmacokinetic parameters for 6-mercapt opurine. We also compared these values with the same parameters from one su bject with low TPMTase activity phenotype. The mean observed area under the plasma concentration-time curve (AUC) was 190 +/- 140 ng mL(-1) h and the elimination rate constant (K-el) was 1.92+/-1. The pharmacokinetic parameters (AUC, K-el, t1/2(el) (the elimination half-l ife)) of 6-mercaptopurine in transplant patients are normally distributed a nd suitable for acceptance as a gold standard value for this population of Caucasian transplant patients. It seems useful to calculate these parameter s, representative of the systemic exposure of individual patients to the dr ug, before prescribing these subjects azathioprine immunosuppressive treatm ent. In subjects with low TPMTase phenotype these pharmacokinetic measureme nts could also be an index of dose reduction.