Most commonly sold under the brand name Imuran, Azathioprine, an immunosuppressant, belongs to the drug class of thiopurines that works by suppressing blood cells that cause inflammation. Available in tablet form for oral administration, Imuran treats rheumatoid arthritis and some other inflammatory conditions. Each tablet contains 50mg Azathioprine and some inactive ingredients. As there are risks of malignancy in humans, physicians administering Imuran should be well aware of Azathioprine metabolism and associated risks, and pharmacogenomics testing, commonly known as PGx testing may help your doctor suggest the correct doses, hence minimizing the risks of adverse effects.

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.

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.

Azathioprine Metabolism and 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.

References:

https://www.ncbi.nlm.nih.gov/books/NBK100661/
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf

 

 

Disclaimer: This blog is only for informational purposes. Please ALWAYS consult a doctor before taking any medical action.