Explain TPMT pharmacogenomics and why testing is recommended before initiating azathioprine or 6-mercaptopurine therapy.

• A. TPMT activity is unaffected by genetics; routine testing unnecessary.
• B. TPMT testing determines drug absorption.
• C. TPMT activity varies genetically; low activity risks myelosuppression; testing guides dosing to reduce toxicity.
• D. TPMT only affects hepatic clearance; not relevant to azathioprine.

Answer: (C)

TPMT is a genetically variable enzyme that metabolizes thiopurines such as azathioprine and 6-mercaptopurine. People carry different TPMT gene variants that can give normal, intermediate, or low enzyme activity. When TPMT activity is low, more active thioguanine metabolites accumulate in the bone marrow, markedly increasing the risk of myelosuppression (neutropenia, anemia). Because of this, testing a patient’s TPMT status before starting thiopurines allows dosing to be tailored to reduce toxicity while preserving effectiveness. If TPMT activity is normal, standard dosing is usually appropriate; if activity is intermediate, dose reduction is typically needed; if activity is low, a substantial dose reduction or alternative therapy may be necessary. Testing can be genotyping common variant alleles or phenotyping enzyme activity, and guidelines support using the results to guide initial dosing and monitoring. This approach minimizes the risk of severe hematologic toxicity and enhances safety when initiating azathioprine or 6-MP.