Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics

Chang, Ji Young; Cheon, Jae Hee

doi:10.1007/s10620-019-05720-5

Cited by 23 publications

(22 citation statements)

References 94 publications

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“…Monitoring of thiopurine metabolites is a part of the safe treatment strategy and, together with other actions, such as the pretreatment screening for virus infections, a routine monitoring of leucocytes and aminotransferase, dose splitting strategies, allopurinol supplementation, and testing for TPMT deficiency, it helps reduce the risk of side-effects [11]. improve the adherence rates [12].…”

Section: Discussionmentioning

confidence: 99%

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

Bąk-Drabik

Adamczyk

Duda-Wrońska

et al. 2021

Gastroenterology Research and Practice

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Introduction. Thiopurines, such as azathioprine (AZA) and 6-mercaptopurine (6-MP), are immunomodulatory agents, used for the maintenance of remission in children with inflammatory bowel disease (IBD)—Crohn’s disease (CD) and ulcerative colitis (UC), as well as with autoimmunological hepatitis (AIH). Measurements of thiopurine metabolites may allow identifying patients at risk for toxicity and nonadherence. It can also provide an explanation for the ineffectiveness of the treatment, observed in some patients. Patients and Methods. A retrospective analysis was carried out of sixty-eight patients (thirty-six patients with CD, eighteen with UC, and fourteen with AIH), treated with AZA. Thiopurine metabolites, 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP), were assayed by high-performance liquid chromatography (HPLC), and the AZA dose was adjusted when 6-TGN concentration was known. Result. Only twenty-five (41%) children had therapeutic 6-TGN concentrations, ten (16%) subjects had suboptimal 6-TGN concentrations, and twenty-six subjects (43%) had 6-TGN concentrations above the recommended therapeutic range. 6-MMP was not above the therapeutic range in any case. Seven subjects revealed undetectable 6-TGN and 6-MMP levels, indicating nonadherence. The mean AZA dose after the 6-TGN concentration-related adjustment did not differ, in comparison to the initial dose, either in IBD or AIH groups. The mean AZA dose was lower in AIH than in IBD. The subjects with an optimal 6-TGN level presented with a higher ratio of remission (88%) than the under- or overdosed patients (60% and 69%), respectively ( Chi − square test = 3.87 , p < 0.05 ). Conclusion. Timely measurements of thiopurine metabolites can be a useful tool to identify nonadherent patients before a decision is taken to switch to another drug. We may also spot the patients who receive either too low or too high doses, compensating dose deviations in an appropriate way. The patients with optimal 6-TGN levels presented a higher percentage of remission than the under- or overdosed patients. In most patients, both initial and adjusted AZA doses, lower than suggested in guidelines, appeared to be sufficient to maintain remission.

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Section: Discussionmentioning

confidence: 99%

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

Bąk-Drabik

Adamczyk

Duda-Wrońska

et al. 2021

Gastroenterology Research and Practice

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“…Thiopurine is administered for maintenance of remission and is used as a steroid-sparing treatment for IBD. Approximately 25% of patients experience thiopurine-induced toxicities, especially myelosuppression [ 18 ]. The first study that reported the association between NUDT15 polymorphisms and 6-MP-induced toxicities was the GWAS conducted in Korean patients with Crohn’s disease.…”

Section: Nudt15 Variants and Toxicities In Thiopurine Metabolismmentioning

confidence: 99%

Importance of NUDT15 Polymorphisms in Thiopurine Treatments

Tanaka

Saito

2021

JPM

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Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.

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“…Genes such as MOCOS, NUD15, and FTO are thought to be involved in the metabolism of AZA [ 24 , 25 , 26 , 27 ]. The MOCOS gene (molybdenum cofactor sulfurase) is thought to have an action on the enzymes AOX1 and XDH [ 25 , 28 ], while the NUD15 gene (nucleoside diphosphate linked moiety X type 15) dephosphoryl 6-TGTP into 6-TGMP [ 27 , 29 ]. As for the FTO gene (fat mass and obesity associated), it could be a potential pharmacogenetic biomarker for treatment with thiopurine [ 24 ].…”

Section: Azathioprine and 6-mercaptopurinementioning

confidence: 99%

“…These elevated levels of 6-MMP tend to increase hepatotoxicity, causing the 6-MMP/6-TGN ratio to increase; which results in a low therapeutic efficacy [ 47 ]. Thus, the identification of patients with asymmetric metabolism would be a major asset for improving the therapeutic response and above all reducing adverse events [ 29 , 48 ].…”

Section: Azathioprine and 6-mercaptopurinementioning

confidence: 99%

Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT

Harmand

Solassol

2020

Genes

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Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.

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Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics

Cited by 23 publications

References 94 publications

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

Importance of NUDT15 Polymorphisms in Thiopurine Treatments

Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT

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