The recent work of Mircheva et al. (1) provides further evidence that azathioprine metabolism is an important factor in the therapeutic use of this active immunosuppressive agent. The authors found a lower incidence of acute rejection among patients in whom erythrocyte thiopurine methyl-transferase (TPMT) activity rapidly increased with the initiation of azathioprine therapy and continued to rise at 3 months after transplantation, compared with patients with stable activity. The authors correctly conclude that the inducibility of erythrocyte TPMT is worthy of further investigation as an important variable for the therapeutic drug monitoring of patients receiving azathioprine. However, their results suggest compliance with azathioprine as a potential explanation for poor therapeutic response. In a study of children with acute lymphoblastic leukemia, a median 32% increase in erythrocyte TPMT activity was observed after the start of thiopurine therapy (2). Furthermore, initiation of thiopurine therapy increased TPMT activity in 94% of patients, including 9/10 children with leukemia and 8/8 adults undergoing cardiac transplantation (2, 3). Activity decreased after cessation of thiopurine therapy in 51/53 (96%) children with leukemia (2, 4). The finding of higher TPMT activity in patients receiving thiopurine therapy is consistent with induction of the enzyme in the presence of substrate (5). As Mircheva et al. had such a large number of patients (41%) without any increase in TPMT activity, the absence of substrate (noncompliance) must be suspected. The inducibility of erythrocyte TPMT may be not only an important marker for monitoring azathioprine therapy, but also a useful measure of drug compliance.
What is missing from the analysis of Mircheva et al. are recommendations for the prospective use of TPMT activity as a potential guide for dosage requirements of the individual patient. By definition, observational approaches that assess the degree of change in TPMT activity require that patients will have received greater than 1 month of therapy before meaningful data will be available. A more useful approach would use the patient's pretransplant value to predict the contribution of TPMT activity toward acute rejection and graft loss. Is there a difference in acute rejection and/or graft loss in patients with greater than median pretherapy TPMT activity versus those with less than the median value?
The variable metabolism of thiopurine drugs by TPMT provides a potential mechanism for variable patient response. It is only through further thoughtful studies, such as that by Mircheva et al., that optimization of therapy for the individual patient can be achieved.
Howard L. McLeod1; Ajay Kumar
Department of Medicine; University of Aberdeen; Aberdeen AB9 2ZD, Scotland
REFERENCES
1. Mircheva J, Legendre C, Soria-Royer C, Thervet E, Beune P, Kreis H. Monitoring of azathioprine-induced immunosuppression with thiopurine methyltransferase activity in kidney transplant recipients. Transplantation 1995; 60: 639.
2. McLeod HL, Relling MV, Liu Q, Pui C-H, Evans WE. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995; 85: 1897.
3. Schütz E, Gummert J, Mohr FW, Armstrong VW, Oellerich M. Azathioprine myelotoxicity related to elevated 6-thioguanine nucleotides in heart transplantation. Transplant Proc 1995; 27: 1298.
4. Lennard L, Lilleyman JS, Van Loon JA, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990; 336: 225.
5. McLeod HL. Commentary on interactions between 6-mercaptopurine therapy and thiopurine-methyl-transferase activity. Eur J Clin Pharmacol 1995; 48: 85.
