Azathioprine is an immunosuppressant which belongs to the drug class of thiopurines that works by suppressing blood cells that cause inflammation. Available in tablet form for oral administration, available in the US under the brand name Imuran. Azathioprine treats rheumatoid arthritis, and some other inflammatory bowel conditions. Available in tablet form (for oral administration) and injection form (for intravenous administration). Tablets have been available in 25mg, 50mg, and 100mg Azathioprine, whereas the injection strength is 100mg/ml. However, as per the latest FDA data, Imuran injections (AZATHIOPRINE SODIUM) as well as the 25mg tablets have been discontinued. As there are risks of malignancy in humans, particularly of the skin, physicians administering Azathioprine should be well aware of its metabolism associated risks.

According to the FDA label, “IMURAN should not be given during pregnancy without careful weighing of risk versus benefit.” Do not administer to pregnant women for treating arthritis.

Indications and Usage:

Kidney transplant rejection, and Rheumatoid Arthritis have been indicated in the FDA label, whereas, Crohn disease, Lupus nephritis, and Ulcerative Colitis are the off-label ones.

Renal Homotransplantation: IMURAN serves as an adjunct to prevent rejection in renal homotransplantation. Data from over 16,000 transplants indicate a 5-year patient survival rate between 35% and 55%. However, survival outcomes depend on factors such as donor compatibility, HLA antigen match, presence of anti-donor or anti-B-cell alloantigen antibodies, and other variables. The impact of IMURAN on these factors has not been evaluated in controlled trials.

Rheumatoid Arthritis: IMURAN is indicated for active RA to help reduce signs and symptoms. During IMURAN treatment, patients may continue using aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and/or low-dose glucocorticoids. However, the combined use of IMURAN with disease-modifying anti-rheumatic drugs (DMARDs) has not been studied for potential added benefits or unforeseen adverse effects. Therefore, it is not recommended to be used along DMARDs.

CONTRAINDICATIONS:

IMURAN should not be administered to patients with known hypersensitivity to the drug. It is contraindicated for treating rheumatoid arthritis in pregnant women. Additionally, patients with RA who have previously received alkylating agents (such as cyclophosphamide, chlorambucil, or melphalan) may face a significantly increased risk of malignancy if treated with IMURAN.

Azathioprine Metabolism

Azathioprine is an immunosuppressive medication that is metabolized into 6-mercaptopurine (6-MP) in the liver through a glutathione-dependent process facilitated by glutathione-S-transferase. 6-MP is subsequently converted into active metabolites, including 6-thioguanine nucleotides (6-TGNs), which are incorporated into DNA, contributing to the drug’s cytotoxic effects. The metabolism of 6-MP involves several enzymes, notably thiopurine S-methyltransferase (TPMT) and xanthine oxidase (XO), which play roles in its inactivation pathways. According to the FDA label, “Maximum serum radioactivity occurs at 1 to 2 hours after oral 35Sazathioprine and decays with a half-life of 5 hours.”

Imuran (Azathioprine) Ingredients

Each scored tablet of Imuran contains 50 mg of the active ingredient azathioprine. The inactive ingredients include lactose, magnesium stearate, potato starch, povidone, and stearic acid.

Genes or Enzymes Involved in Azathioprine’s Metabolism

The primary enzymes involved in azathioprine metabolism are:

• Thiopurine S-methyltransferase (TPMT): Catalyzes the methylation of 6-MP to inactive metabolites. Genetic polymorphisms in the TPMT gene can lead to variations in enzyme activity, affecting drug toxicity and efficacy.
• Xanthine Oxidase (XO): Involved in the oxidation of 6-MP to inactive metabolites.
• Hypoxanthine-guanine phosphoribosyltransferase (HGPRT): Facilitates the conversion of 6-MP to active metabolites, including 6-TGNs.

Additionally, genetic polymorphisms in the NUDT15 gene have been associated with variations in azathioprine metabolism, particularly in certain populations. Variants in NUDT15 can lead to increased sensitivity to the drug and a higher risk of myelosuppression.

Effects of Azathioprine on Normal Metabolizers

Individuals with normal TPMT activity (homozygous for functional alleles) typically metabolize azathioprine efficiently, maintaining a balance between active and inactive metabolites. This balance generally allows for effective immunosuppression with a standard dosing regimen and a lower risk of adverse effects.

Effects of Azathioprine on Intermediate Metabolizers

Intermediate metabolizers possess one functional and one non-functional TPMT allele, resulting in reduced enzyme activity. These individuals may have higher levels of active metabolites (6-TGNs), increasing the risk of myelotoxicity, such as leukopenia. Dose adjustments and careful monitoring are recommended to mitigate potential toxicities in these patients.

Imuran Drugs Interactions:

1. Use with Xanthine Oxidase (XO) Inhibitors

Azathioprine is broken down in the body through a process that can be blocked by XO inhibitors like allopurinol and febuxostat.

Allopurinol: If taken together with IMURAN, the dose of IMURAN should be reduced to 1/3 or 1/4 of the usual amount.

Febuxostat: Should not be used with IMURAN.

Patients with low or no TPMT enzyme activity: Since both TPMT and XO pathways help break down IMURAN, extra dose reductions or alternative treatments should be considered.

2. Use with Aminosalicylates

Certain anti-inflammatory drugs used for bowel diseases, such as sulphasalazine, mesalazine, or olsalazine, may reduce TPMT enzyme activity. If used with IMURAN, extra caution is needed.

3. Use with Drugs Affecting White Blood Cell Production

Some medications, such as co-trimoxazole, may significantly lower white blood cell levels, especially in kidney transplant patients.

4. Use with Angiotensin-Converting Enzyme (ACE) Inhibitors

ACE inhibitors, commonly used for high blood pressure, may cause anemia and severe white blood cell reduction (leukopenia) when taken with IMURAN.

5. Use with Warfarin

IMURAN may reduce the blood-thinning effects of warfarin, possibly making it less effective.

6. Use with Ribavirin

Ribavirin, a drug for hepatitis C, may cause severe blood cell reduction (pancytopenia) when taken with IMURAN.

• Ribavirin blocks an enzyme (IMDH) needed for one of IMURAN’s breakdown pathways. This can lead to a toxic buildup of 6-MTITP, a substance linked to low white blood cells (neutropenia), low platelets (thrombocytopenia), and anemia.
• Patients using both drugs should have frequent blood tests:
  1. Weekly for the first month
  2. Twice a month for the second and third months
  3. Monthly or more often if the dose or treatment plan changes.

 

Did you know?

Adverse drug reactions are preventable. NIH states that over 1.25 million serious adverse events were reported in 2022 only.

Thioguanine Nucleotides Activation & PGx

According to Pubmed, “Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites.” The enzyme nudix hydrolase 15 (NUDT15) and thiopurine methyltransferase (TPMT) activate and inactivate the active metabolites of this medicine. Thus, people who are intermediate metabolizers of either of these enzymes are at higher risk of adverse effects. The FDA label for azathioprine recommends TPMT testing (genotype or phenotype) before starting treatment. It is important to note that the most common non-functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C, while in the case of the TPMT and NUDT15 genes, our test currently shows genotype *1/*1 only.

An at-home PGx test by RPh LABS gives insights into your genome (set of all DNA) and shows how your body may respond to 250+ medications. Thus, allowing your doctor to prescribe drugs and dosages as per your genetic makeup.

Conclusion:

Azathioprine metabolism depends on TPMT, NUDT15, XO, and HGPRT enzymes, which regulate its activation (6-TGNs) and inactivation pathways. TPMT and NUDT15 intermediate metabolizers are at higher risk due to increased accumulation of toxic 6-TGNs. Thus, the FDA label clearly states for TPMT testing as “consideration be given to either genotype or phenotype patients for TPMT.” However, it should be kept in mind that a TPMT test CANNOT substitute for a complete blood count (CBC) test in patients who are being administered Azathioprine.