Clinical Information

Thiopurine methyltransferase (TPMT) deficiency is a condition in which patients treated with standard doses of azathioprine (AZA, Imuran), 6-mercaptopurine (6-MP, Purinethol), or 6-thioguanine (6-TG, Thioguanine Tabloid) may develop life-threatening myelosuppression or severe hematopoietic toxicity. The metabolic conversion of AZA, 6-MP, or 6-TG to purine nucleotides and the subsequent incorporation of these nucleotides into DNA play an important role in both the therapeutic efficacy and toxicity of these drugs. A competitive catabolic route for the metabolism of thiopurines is catalyzed by the TPMT enzyme, which inactivates them by thiomethylation. A balance must be established between these competing metabolic pathways so that sufficient amounts of drug are converted to the nucleotide to act as an antimetabolite and antimetabolite levels do not become so high as to cause potentially lethal bone marrow suppression.

Thiopurine methyltransferase deficiency is inherited as a codominant trait, and variable TPMT activity is associated with TPMT genetic variants. The distribution of TPMT activity in red blood cells is trimodal in the population of people with European ancestry, with approximately 0.3% having deficient (undetectable) TPMT activity, 11% low (intermediate) activity, and 89% normal TPMT activity.. Adverse effects of AZA, 6-MP, or 6-TG administration can be observed in individuals with severe or intermediate TPMT deficiency.

Thiopurine methyltransferase hyperactivity is also a known phenotype. Individuals who are hypermetabolizers have therapeutic resistance to thiopurine drugs and therefore, cannot achieve therapeutic levels. If an individual with TPMT hyperactivity is treated with higher and higher doses of thiopurine drugs, they may develop severe hepatotoxicity. Therefore, treatment with alternative medications is recommended for hypermetabolizers.

As such, knowing a patient's TPMT status prior to treatment with AZA, 6-MP, or 6-TG is important for purposes of calculating safe drug dosages for therapy.