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

David E. Jonason, Tyson Sievers, Lindsay Trocke, James M. Abraham, Byron P. Vaughn

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalCrohn's and Colitis 360
Volume2
Issue number3
DOIs
StatePublished - Jul 1 2020

Bibliographical note

Publisher Copyright:
© 2020 Crohn’s & Colitis Foundation.

Keywords

  • 6-thioguanine nucleotide
  • Azathioprine
  • Inflammatory bowel disease
  • Therapeutic drug monitoring
  • Thiopurine methyltransferase

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