Patients deficient in the TPMT enzyme, even making use of recommended doses, due to lack of inactivation of the 6-MP metabolites, can have a tissue accumulation of the drug and consequently adverse effects, mainly related to myelosuppression23. In fact, thiopurines have a very narrow therapeutic index, which means that the maximum tolerated dose is very close to that capable of generating an adverse effect. Hence, it is of fundamental importance to recognize the factors that may increase the risk of toxicity of these drugs. One of them is the polymorphism of the TPMT enzyme, which converts 6-MP into an inactive metabolite. Patients with partial and complete TPMT deficiency are at high risk of intolerance to the use of thiopurines26. Studies have shown that about 10% to 20% of the population has partial deficiency and about 0.5% has complete TPMT deficiency26- …show more content…
Allergic reactions to AZA or 6-MP typically occur within two to four weeks of start of therapy, and include fever, skin rash, myalgias, abdominal pain, pancreatitis and toxic hepatitis, which usually resolve with discontinuation of therapy28 -31. Other adverse effects related to the use of thiopurines such as pancreatitis, hepatitis and even myelosuppression may be associated with the low serum level of the TPMT converting enzyme26,27. Nevertheless, treatment intolerance, whose main complaints are myalgia, nausea and symptoms similar to a common cold (flu-like symptoms) are actually due to another factor. Early intolerance to azathioprine is believed to be derived from imidazole derivatives produced by the cleavage of azathioprine in 6-MP32. This could also explain why AZA-intolerant patients could be tolerant to the 6-MP