The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

Blaker, Paul; Arenas-Hernandez, Monica; Sanderson, Jeremy

doi:10.2217/pme.12.85

Cited by 14 publications

(18 citation statements)

References 173 publications

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“…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].…”

Section: Indroductionmentioning

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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Section: Indroductionmentioning

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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“…Thirdly, mercaptopurine can be catabolised to thiouric acid by xanthine oxidase. Up to 20% of patients preferentially metabolise thiopurines to produce high levels of 6‐MMP and low levels of 6‐TGN 5 . These so‐called ‘thiopurine hypermethylators’ or ‘shunters’ are usually refractory to standard doses of thiopurines and are likely to develop adverse events.…”

Section: Introductionmentioning

confidence: 99%

A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients

Savelkoul

Gabriëls

Simsek

et al. 2020

Aliment Pharmacol Ther

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| on behalf of the Dutch Initiative on Crohn's Colitis (ICC)This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. SummaryBackground: Both tioguanine and low-dose thiopurines combined with allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to adverse events. Aim:To compare the safety of tioguanine and LDTA in IBD patients. Methods:Inflammatory bowel disease patients who failed conventional thiopurines due to adverse events and initiated LDTA in standard care were identified in the prospective ICC Registry. IBD patients who failed conventional thiopurines due to adverse events and initiated tioguanine were enrolled in three university hospitals.Patients on concomitant biologicals were excluded. The primary outcome was discontinuation of therapy due to adverse events. Secondary outcomes included: safety outcomes and surgery-, biological-and corticosteroid-free clinical remission (physician global assessment = 0) after 104 weeks. Both multiple logistic regression and propensity score matching were used to correct for confounders. Results:In total, 182 IBD patients treated with tioguanine (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91-104). Of these, 19% (tioguanine: 20%, LDTA: 18%) of patients discontinued therapy due to adverse events. After adjusting for confounders, there were no differences in terms of discontinuation rate due to adverse events (OR 0.50, 95% CI 0.15-1.68, P = 0.26), adverse events (OR 0.89, 95% CI 0.44-1.81, P = 0.75), infections (OR 1.05, 95% CI 0.40-2.73, P = 0.93), hospitalisations (OR 2.00, 95% CI 0.64-6.23, P = 0.23) or clinical remission (OR 0.74, 95%CI 0.33-1.68, P = 0.48). All results are comparable with the propensity score matched cohort.

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“…Leukopenia is the primary adverse drug response that disrupts treatment and the susceptibility to 6-MP differs between European and Japanese ancestry populations. In European-descent patients, thiopurine S-methyltransferase (TPMT) deficiency increases susceptibility to leukopenia where homozygous and heterozygous recessive patients require lower dosages of 6-MP (Blaker et al, 2012). Similarly, nucleoside diphospatase-15 (NUD15) deficiency increases the risk for leukopenia in patients of Japanese descent .…”

Section: Discovery Toxicology Screeningmentioning

confidence: 99%

Principles of precision medicine and its application in toxicology

Cook

Aleo

et al. 2018

J. Toxicol. Sci.

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Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug's mode-of-action. Nonclinical models such as the mouse and non-human primate can be used to understand genetic variation and its potential translation to humans, and are available for toxicologists to employ in advance of drugs moving into clinical development. Understanding interindividual differences in response to drugs and how these differences can influence the drug's risk-benefit profile and lead to the identification of biomarkers that enhance patient efficacy and safety is of critical importance for toxicologists today, and in the future, as the fields of pharmacogenomics and genetics continue to advance. Abbreviations 6-MP = 6-mercaptopurine ADME = Absorption, distribution, metabolism, and excretion ALT = Alanine aminotransferase CETPi = Cholesterol ester transfer protein inhibitor CNV = Copy number variant CYP = Cytochrome P450 GOF = Gain of function DILI = Drug-induced liver injury GWAS = Genome-wide association studies HDL = High-density lipoprotein HIV = Human immunodeficiency virus INDELS = Insertion and deletion LOF = Loss of function MMHP = Mouse model of the human population MOA = Mode-of-action MPS = Microphysiological system MDR = Multidrug resistence MRP = Multidrug resistance-associated protein OATP = Organic anion transporting polypeptide NUD15 = Nucleoside diphosphatase-15 NSCLC = Non-small cell lung carcinoma R&D = Research and Development SLCO = Solute carrier organic anion SNPs = Single nucleotide polymorphisms TPMT = Thiopurine S-methyltransferase VLDL = Very-low density lipoprotein

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The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

Cited by 14 publications

References 173 publications

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

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

A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients

Principles of precision medicine and its application in toxicology

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