Reducing risk in thiopurine therapy

Xenobiotica. 2020 Jan;50(1):101-109. doi: 10.1080/00498254.2019.1688424. Epub 2019 Nov 12.


The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. NUDT15 variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.

Keywords: NUDT15; TPMT; Thiopurine; azathioprine; mercaptopurine; thioguanine nucleotide; thiopurine methyltransferase.

Publication types

  • Review

MeSH terms

  • Azathioprine / adverse effects
  • Azathioprine / therapeutic use
  • Drug Hypersensitivity / genetics*
  • Erythrocytes
  • Female
  • Genotype
  • Humans
  • Male
  • Mercaptopurine / adverse effects
  • Mercaptopurine / analogs & derivatives
  • Mercaptopurine / therapeutic use
  • Methyltransferases
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Purine-Pyrimidine Metabolism, Inborn Errors / genetics*
  • Purines / adverse effects
  • Purines / therapeutic use*


  • Purines
  • 6-methylthiopurine
  • Mercaptopurine
  • Methyltransferases
  • Azathioprine

Supplementary concepts

  • Thiopurine S methyltranferase deficiency