Safety of Thiopurine Therapy in Inflammatory Bowel Disease

Chaparro, María; Ordás, Íngrid; Cabré, Eduard; García–Sánchez, Valle; Bastida, Guillermo; Peñalva, Mireia; Gomollón, Fernando; García‐Planella, Esther; Merino, Olga; Gutiérrez, Ana; Esteve, María; Márquez, Lucía; García-Sepulcre, M F; Hinojosa, Joaquín; Vera, Isabel; Muñoz, Fernándo; Mendoza, Juan L.; Cabriada, José Luis; Montoro, Miguel; Acosta, Manuel Barreiro‐de; Ceña, Gloria; Saro, Cristina; Aldeguer, Xavier; Barrio, Jesús; Maté, José; Gisbert, Javier P.

doi:10.1097/mib.0b013e318281f28f

Cited by 262 publications

(159 citation statements)

References 38 publications

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“…Around 4-7% of IBD patients develop pancreatitis within 3 months of commencing thiopurine therapy [5,88], and in most cases this adverse effect necessitates withdrawal of therapy. Until recently, no convincing genetic predictors of thiopurine-related pancreatitis had been identified.…”

Section: A Role For An Hla-dqa1-hla-drb1 Snp In Predicting Pancreatitismentioning

confidence: 99%

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Roberts

Barclay

2015

Pharmacogenomics

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Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

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Section: A Role For An Hla-dqa1-hla-drb1 Snp In Predicting Pancreatitismentioning

confidence: 99%

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Roberts

Barclay

2015

Pharmacogenomics

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Section: Indroductionmentioning

confidence: 99%

“…However, the occurrence of adverse drug reactions limits the use of these drugs. Up to 15 % of IBD patients discontinue this type of treatment due to adverse events that include nausea, skin reactions, pancreatitis, hepatotoxicity or myelotoxicity [6,7].Thiopurine drugs are prodrugs, so their biological activity is preceded by extensive metabolism. Briefly, after absorption, AZA is metabolized in the liver to 6-MP which then can be metabolized to active thioguanine nucleotides (TGN) and to inactive methylated product 6-methylmercaptopurine (6-MMP) by the thiopurine-S-methyl transferase (TPMT) enzyme [8].…”

mentioning

confidence: 99%

Determination of thiopurine S -methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry

Pecher

Dokupilová

Zelinková

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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Determination of thiopurine S-methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry, Journal of Pharmaceutical and Biomedical Analysishttp://dx.doi.org/10. 1016/j.jpba.2017.05.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Highlights New HILIC-HPLC-MS method was developed for determination of TPMT activity  HILIC-HPLC-MS combination was approved by excellent performance parameters  HILIC-HPLC-MS was compared to traditional RP-HPLC-UV as well as advanced RP-HPLC-MS  Conventional approaches were surpassed in terms of selectivity, LOD, analysis time  HILIC-HPLC-MS is favorable for routine assay of 6-MMP/6-MP ratio in RBC lysates List of abbreviations6-MMP -6-methylmercaptopurine, 6-MP -6-mercaptopurine, 6-TG -6-thioguanine, AZA -azathioprine, Cl-P -6-chloropurine, DTT -dithiothreitol, IBD -inflammatory bowel diseases, RBC -red blood cells, SAM -S-adenosyl-L-methionine, TGN -thioguanine nucleotides, TPMT -thiopurine-S-methyl transferase. IndroductionThiopurine drugs, namely azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are immunosuppressive agents that are, due to their low cost and high effectiveness, widely used in the treatment of inflammatory bowel diseases (IBD), but also in other autoimmune diseases, some hemopoetic disorders and some solid organ transplant [1][2][3][4][5]. However, the occurrence of adverse drug reactions limits the use of these drugs. Up to 15 % of IBD patients discontinue this type of treatment due to adverse events that include nausea, skin reactions, pancreatitis, hepatotoxicity or myelotoxicity [6,7].Thiopurine drugs are prodrugs, so their biological activity is preceded by extensive metabolism. Briefly, after absorption, AZA is metabolized in the liver to 6-MP which then can be metabolized to active thioguanine nucleotides (TGN) and to inactive methylated product 6-methylmercaptopurine (6-MMP) by the thiopurine-S-methyl transferase (TPMT) enzyme [8]. TPMT (EC 2.1.1.67), a key enzyme involved in the thiopurine drug metabolism, is subject to common genetic polymorphism that leads to trimodial distribution of the TPMT activity in population [9]. Individuals with lower TPMT activity might have an increased risk of developing thiopurine-induced myelosuppression. On the contrary, individuals with high TPMT activity have lower concentrations of active TGN metabolites resulting in reduced therapeutic efficacy of the drug [10]. In addition, high TPMT activity leads to accumulation of the hepatotoxic methylated metabolites [11]. Therefore, some scientific committees advise to determine the TP...

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“…The hypersensitivity allergic reaction is neither common (occurs in 1% of patients 45 ), nor TPMT-related, nor dose-dependent, as in the cases of myelosuppression and hepatotoxicity. 46 These unpredictable hypersensitivity reactions typically occur during the first weeks of treatment or after the patient has been weaned from steroids.…”

Section: Immunomodulatorsmentioning

confidence: 99%

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

Cohn

Dave

Loftus

2017

Inflammatory Bowel Diseases

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Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases for which there are no cures. These diseases are immunopathogenic, and medical treatment is centered on the temperance of a dysregulated immune response to allow mucosal healing and prevent the sequelae of fistulation and stenosis. Accordingly, the armamentarium of medications, which has expanded immensely in recent history, is not without significant infectious and neoplastic risks. Many of these untoward effects can be mitigated by screening and avoidance of contraindicated medications. This review seeks to highlight the cautions for use of immunomodulators, anticytokine and α4-integrin antagonists. The potential adverse events are further complicated by substantial heterogeneity in disease phenotype in the IBD population. Large patient registries and databases provide considerable experience and knowledge to calculate the incidence of safety outcomes. To identify rarer outcomes after prolonged therapy, more prospective studies and continued adverse event reporting will aid safe application and minimize potential harms.

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Safety of Thiopurine Therapy in Inflammatory Bowel Disease

Cited by 262 publications

References 38 publications

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Determination of thiopurine S -methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

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