Thiopurine Methyltransferase (TPMT)

Thiopurine methyltransferase (TPMT) is an enzyme that breaks down (metabolizes) thiopurines. Thiopurines include three medications: 6- mercaptopurine (6-MP), 6-thioguanine (6-TG), and azathioprine. 6-MP and 6-TG are often used to treat leukemia or lymphoma. Like many drugs, their effectiveness and side effects can vary from person to person. One of the reasons why this difference occurs is because each person’s ability to metabolize thiopurines is different based on variations in the TPMT gene. Every person can be classified into one of 3 possible genotype groups. We use a different starting dose of 6-MP and 6-TG for the different genotype groups. By changing the dose based on a patient’s genotype, there are fewer side effects (due to low blood counts).

Priority genotypes

Intermediate metabolizers – means there is one normal, functioning copy of the gene and one no-function copy of the gene. Patients have decreased TPMT function and may require reduced doses of thiopurine medications to avoid side effects. About 1 in 10 people have this genotype.

• Azathioprine: Consider reducing the dose of azathioprine to 0.6 to 2 mg/kg/day.
• Mercaptopurine: Consider starting mercaptopurine doses at 30 to 70% of the normal dose.
• Thioguanine: Consider starting thioguanine doses at 30 to 50% of the normal dose.

Poor metabolizers – means there are two copies of the no-function gene and there is no normal TPMT enzyme. These patients are at a very high risk of experiencing toxicity (low blood counts) from 6-MP or 6-TG or azathioprine. Patients should receive substantially lower doses than normal to avoid side effects of low blood counts. About 1 in 400 people have this very high risk priority genotype.

• Azathioprine: Consider an alternative agent or reducing the dose of azathioprine by 90% and administer three times per week instead of daily.
• Mercaptopurine: For non-malignant conditions, consider alternative agents; for malignancy, reduce the dose of mercaptopurine by 90% and administer three times per week instead of daily.
• Thioguanine: Consider an alternative agent or reducing the dose of thioguanine by 90% and administer three times per week instead of daily.

Routine genotype

Normal metabolizers – means there are two copies of the normal, functional gene. This results in normal TPMT function. About 9 in 10 people have this genotype. No change in thiopurine dose is recommended based on this genotype.