A Physician's Guide to Azathioprine Metabolite Testing

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the maintenance of disease remission in patients with inflammatory bowel disease. Inherent differences in drug metabolism based on genetic polymorphism in thiopurine methyl transferase (TPMT) activity, the key catabolic enzyme in 6-MP metabolism, have been shown to influence patient responsiveness to therapy. Indeed, tailoring the dose of AZA based on TPMT activity has been proposed as a useful clinical tool to improve overall clinical response and to avoid untoward side effects. Recent studies have shown that patients with intermediate TPMT activity should be initiated on a low (1 mg/kg) dosage of AZA and carefully monitored in order to minimize the risk of bone marrow suppression. Patients with very high TPMT enzyme activity levels (>15 U/mL) may very well respond to a higher (>2 mg/kg) dosage of AZA. However, these patients may remain refractory to conventional-dose therapy by shunting 6-MP metabolism away from the production of its active 6-thioguanine (6-TGn) nucleotide metabolite. Individualized AZA dosing based on TPMT enzyme activity is based on the notion of achieving therapeutic erythrocyte 6-TGn metabolite levels between 235-260 pmol/8×10⁸ red blood cells. Future prospective controlled trials are still needed to validate the universal application of drug monitoring strategies in clinical practice.