Purines thiopurine methyltransferase

Deininger M, Szumlanski CL, Otter-ness DM et al. Purine substrates for human thiopurine methyltransferase. Bio-chem Pharmacol 1994 48 2135-2138. 

Azathoiprine is metabolised to 6-mercaptopurine (see p. 608), which is responsible for many, but not all, of its actions as an inhibitor of purine synthesis. The cellular immune response is impaired, notably the function of both B and T lymphocytes. As a result of a genetic polymorphism, approximately 1 in 300 Caucasian people have very low levels of thiopurine methyltransferase (TPMT) the enzyme that metabolises 6-mercaptopurine these individuals are at high risk of toxicity to normal doses of azathioprine. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn s disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1-1.5 mg/kg/d, or azathioprine, 2-2.5 mg/kg/d. After 3-6 months of treatment, 50-60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority. 

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