Azathioprine with Allopurinol

Coulthard, Sally A.; Berry, Phil; McGarrity, Sarah; McLaughlin, Simon D.; Ansari, Azhar; Redfern, Christopher P.F.

doi:10.1097/mib.0000000000001131

Cited by 8 publications

(2 citation statements)

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“…Curffari et al[36] also discovered that the levels of DNA-TG metabolites were correlated with the erythrocyte 6TGN level, but not the total leukocyte level. However, a recent study performed by Coulthard et al[37] showed contradictory results, indicating that the exact function of DNA-TG still requires further validation in IBD. On the other hand, we performed this retrospective research to determine the cut-off levels of 6TGN for predicting TIL, which need to be validated in further prospective studies.…”

Section: Discussionmentioning

confidence: 99%

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Zhu¹,

Chao²,

Li³

et al. 2019

WJG

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BACKGROUNDThiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIMTo determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODSPatients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.RESULTSA total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.CONCLUSIONThe predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

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Section: Discussionmentioning

confidence: 99%

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Zhu¹,

Chao²,

Li³

et al. 2019

WJG

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“…Allopurinol is a xanthine oxidase inhibitor and when added to TP increases its metabolism through 5-IMPDH into 6-TGN. LDTA can be useful in "hypermethylators" (79), in which TGN levels are usually <230-400 pmol/8 × 10 8 and/or 6-MMP levels are over 5,700-6,000 pmol/8 × 10 8 (80), so that they are at risk of hepatotoxicity and refractoriness to TP (81).…”

Section: Using Low Dose Thiopurine and Allopurinolmentioning

confidence: 99%

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

2021

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Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.

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Drug Interactions in the Liver

Aithal

Kullak‐Ublick

2020

The Liver

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Azathioprine with Allopurinol

Abstract: Article first published online 27 April 2017Supplemental Digital Content is Available in the Text.

Cited by 8 publications

References 50 publications

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

Drug Interactions in the Liver

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