Azathioprine (Imuran® and generic products) is a prodrug, meaning it is inactive as it is given and must be converted to an active form, 6-mercaptopurine (6-MP), by your body in order to have any effect. Azathioprine is a drug that is similar to the DNA bases found normally in the body, and it helps to stop making certain harmful cells in your body.

Azathioprine is commonly used with other drugs to prevent rejection of a kidney transplant, as well as for the treatment of conditions like rheumatoid arthritis (RA), lupus nephritis, and psoriatic arthritis. This medication should not be given to pregnant women or patients who experience side effects when given 6-MP, as azathioprine is converted to 6-MP within the body.

The gene of interest with regard to both azathioprine and 6-MP is Thiopurine S-methyltransferase (TPMT). This gene is responsible for producing a substance called an enzyme that inactivates the drug, which is the first step in clearing it from the body. Changes in this gene can lead to less drug being inactivated, resulting in more active drug being in the body and staying in the body for a longer period of time. This may result in severe side effects including an increased risk of infection.

There are at least 15 known variations of the TPMT gene. Patients with two TPMT genes (one from each parent) that make the less active enzyme are at the highest risk of azathioprine side effects. Patients who have genes that code for one normal enzyme and one nonfunctional enzyme are at a moderate risk of side effects. Patients at the lowest risk for azathioprine side effects are those who have genes coding for two normal enzymes. In order to reduce the risk of life threatening adverse reactions, it is important to adjust the dose of azathioprine given to a patient based on his or her genetic makeup.

An African-American female, Tiffany, starts taking azathioprine for the first time. Her doctor diagnosed her with rheumatoid arthritis and recommended the medication for pain relief. Before writing a prescription for azathioprine, Tiffany’s doctor recommended she consent to a genetic test to determine her TPMT genotype. He explained that this test would help guide the selection of an optimal dose for her, lowering the risk of an adverse effect of azathioprine called myelotoxicity. Tiffany declined the test because she did not want to delay any potential pain relief that azathioprine may offer. Three weeks after starting azathioprine, Tiffany is told she has to stop taking it due to a significant drop in white blood cells, which puts her at increased risk for serious infections. As a result, she will have to be put on a different medication to control her rheumatic arthritis pain.

Six years later, Tiffany’s daughter, Rachel, is undergoing a kidney transplant. To reduce the risk of Rachel’s body rejecting the new kidney, she is prescribed two different medications, one of which is azathioprine. Rachel chooses to have her TPMT genotype checked at her doctor’s request. The test results show that Rachel has inherited a non-functional TPMT gene from both her mother and father. With this information, Rachel’s doctor prescribes her a lower dose of azathioprine, which is more compatible to her TPMT genotype than the typical starting dose. Because she had this genetic test, she will have a lower risk for suffering from myelotoxicitiy while still receiving the full benefit of azathioprine.

TPMT testing will neither completely eliminate the risks of taking azathioprine, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to azathioprine. The links are to external websites and will be checked regularly for consistency.

• Azathioprine Prescribing Information
• Azathioprine Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Azathioprine

Black AJ, McLeod H, Capell HA et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Annals of Internal Medicine. 1998;129:716–8.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Azathioprine; [cited 2012 Oct 23]; [about 3 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59f3219f-898f-4d05-a430-c2b3f5255af1/.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Mercaptopurine; [cited 2012 Oct 9]; [about 3 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=15904472-4c32-4224-95d3-eb131a7ff9c8/.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Azathioprine; [updated 2011 Aug 10; cited 2012 Oct 19]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA448515/.

Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clinical Pharmacology and Therapeutics. 2011 Mar;89(3):387-91.