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Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease

Abstract

The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.

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Acknowledgements

This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP20gm1010008h9904 (AA) and 19ek0410056h0001 (YK), and in part by a Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan under Grant Number 19K08811(MK), 21K07955(YK) and 18K08002(AA), and in part by Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan under Grant Number 20FC1037 (AA).

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Correspondence to Akira Andoh.

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AA receiving lecture fee from Janssen, Takeda, AbbVie, Tanabe-Mitsubishi. All other authors declare that they have no conflict of interest in this study.

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Andoh, A., Kawahara, M., Imai, T. et al. Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease. J Gastroenterol 56, 881–890 (2021). https://doi.org/10.1007/s00535-021-01805-z

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Keywords

  • Inflammatory bowel disease
  • Thiopurine
  • NUDT15