Role of Monitoring Thiopurine Methyltransferase (TPMT) Activity in the Individualized Therapy with Azathioprine or 6-Mercaptopurine

Thiopurine drugs azathioprine and 6-mercaptopurine are inactive compounds that must be metabolized to 6- thioguanine nucleotides to exert their immunosuppressive properties. Hypoxanthine-guanine phosphoribosyltransferase anabolizes 6-mercaptopurine into the 6-thioguanine nucleotides responsible for the therapeutic activity and drug-related leucopenia. On the other hand, thiopurine methyltransferase (TPMT) metabolizes 6-mercaptopurine into inactive methylmercaptopurine. Therefore, reduction in TPMT activity predisposes to bone marrow suppression because of preferential metabolism of 6-mercaptopurine to 6-thioguanine nucleotides. The choice of the dose of azathioprine/6-mercaptopurine is generally based on the patient's weight. However, several strategies have been suggested in choosing, in a more individualized and safer way, the thiopurine dose, with the intention, on one hand, to identify patients at risk of myelotoxicity and, on the other hand, to detect patients with inadequate immunosuppressant. In this respect, quantification of TPMT activity has been considered a promising area, as it may identify unique metabolic profiles in patients at high risk for adverse reaction prior to drug exposure. The aim of the present manuscript is to review the following aspects related with TPMT determination: 1) TPMT activity distribution in general population. 2) Advantages and disadvantages of TPMT genotype and phenotype determination. 3) Relationship between TPMT activity and azathioprine induced myelotoxicity. 4) TPMT activity and immunosuppressive efficacy of azathioprine. 5) How can azathioprine dose be adjusted based on TPMT activity? 6) Is TPMT activity monitoring indicated in all patients who are going to receive azathioprine? 7) Can systematic blood controls be avoided in patients treated with azathioprine if TPMT is determined?