Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations with Azathioprine Therapy in Inflammatory Bowel Disease

Background: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. Methods: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. Results: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 10⁸ red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 10⁸ RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 10⁸ RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. Conclusions: Variations within the normal range of TPMT activity do not affect 6-TGN concentration. Lay Summary Thiopurine methyltransferase (TPMT) activity in the normal or high range does not affect 6-thioguanine nucleotide concentration in patients with inflammatory bowel disease treated with azathioprine. Providers should not make assumptions about 6-thioguanine nucleotide concentration based on normal TPMT activity.