363 results match your criteria Azathioprine Metabolism and TPMT


Intestinal microbiota-mediated biotransformations alter the pharmacokinetics of the major metabolites of azathioprine in rats after oral administration.

Drug Metab Pharmacokinet 2022 Mar 19;45:100458. Epub 2022 Mar 19.

Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China. Electronic address:

Adverse reactions to azathioprine (AZA) vary greatly among individuals, which is associated with the variable levels of its major metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). The intestinal microbiota has been proven to contain AZA-metabolizing enzymes, although the explicit role of the intestinal microbiota in AZA metabolism in vivo remains poorly comprehended. In this study, the pharmacokinetic behaviours of 6-TGN and 6-MMP were assessed in the pseudo germ-free (PGF) group and control group following oral administration of AZA. Read More

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Gut Microbiota Metabolism of Azathioprine: A New Hallmark for Personalized Drug-Targeted Therapy of Chronic Inflammatory Bowel Disease.

Front Pharmacol 2022 5;13:879170. Epub 2022 Apr 5.

Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.

Despite the growing number of new drugs approved for the treatment of inflammatory bowel disease (IBD), the long-term clinical use of thiopurine therapy and the well-known properties of conventional drugs including azathioprine have made their place in IBD therapy extremely valuable. Despite the fact that thiopurine S-methyltransferase (TPMT) polymorphism has been recognized as a major cause of the interindividual variability in the azathioprine response, recent evidence suggests that there might be some yet unknown causes which complicate dosing strategies causing either failure of therapy or toxicity. Increasing evidence suggests that gut microbiota, with its ability to release microbial enzymes, affects the pharmacokinetics of numerous drugs and subsequently drastically alters clinical effectiveness. Read More

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Predicted expression of genes involved in the thiopurine metabolic pathway and azathioprine discontinuation due to myelotoxicity.

Clin Transl Sci 2022 04 20;15(4):859-865. Epub 2022 Feb 20.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

TPMT and NUDT15 variants explain less than 25% of azathioprine-associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. Read More

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TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real-World Clinical Results.

Clin Pharmacol Ther 2022 01 12;111(1):263-271. Epub 2021 Oct 12.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. Read More

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January 2022

Relationship Between Thiopurine S-Methyltransferase Genotype/Phenotype and 6-Thioguanine Nucleotide Levels in 316 Patients With Inflammatory Bowel Disease on 6-Thioguanine.

Ther Drug Monit 2021 10;43(5):617-623

Department of Gastroenterology, Surrey and Sussex NHS, East Surrey Hospital, Surrey, United Kingdom.

Background: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD.

Methods: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Read More

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October 2021

Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients.

Pharmacol Res Perspect 2021 05;9(3):e00764

Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Read More

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Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis.

Expert Rev Clin Pharmacol 2021 Apr 15;14(4):491-501. Epub 2021 Mar 15.

Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

: Prevalence and impact of thiopurine S-methyltransferase () and Nudix hydrolase () minor allele frequencies in South Asian population is unclear.: We searched PubMed and Embase with keywords- and combined with South Asian countries. We included studies reporting frequency of and polymorphisms. Read More

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Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.

J Gastroenterol Hepatol 2021 Aug 29;36(8):2116-2124. Epub 2021 Jan 29.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background And Aim: Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. Read More

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TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience.

Pulm Pharmacol Ther 2021 02 3;66:101988. Epub 2021 Jan 3.

Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address:

Background: The choice of immunosuppressive therapy in interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is based on safety profile and expected efficacy. Azathioprine is one of the most commonly used agents to treat ILD. The immunosuppressive effect and pancreatitis risk of azathioprine are influenced by the activity of the enzyme thiopurine methyltransferase (TPMT) and by the genetic mutations in HLA-DQA1-HLA-DRB locus, respectively. Read More

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February 2021

PharmFrag: An Easy and Fast Multiplex Pharmacogenetics Assay to Simultaneously Analyze 9 Genetic Polymorphisms Involved in Response Variability of Anticancer Drugs.

Int J Mol Sci 2020 Dec 17;21(24). Epub 2020 Dec 17.

IRSET (Institut de Recherche en Santé, Environnement et Travail), University of Rennes, CHU Rennes, EHESP, UMR_S 1085, 35000 Rennes, France.

Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). Read More

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December 2020

The Identification of a Novel Thiopurine S-Methyltransferase Allele, , in Korean Patient with Crohn's Disease.

Pharmgenomics Pers Med 2020 26;13:665-671. Epub 2020 Nov 26.

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Pediatric Crohn's disease (CD) carries a higher genetic susceptibility and an increased risk of a more aggressive disease course than adult CD. Treatment of CD is based on immunomodulatory drugs, such as thiopurines. The enzyme mainly involved in drug metabolism is thiopurine S-methyltransferase (TPMT). Read More

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November 2020

Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation.

Basic Clin Pharmacol Toxicol 2021 Mar 21;128(3):482-492. Epub 2020 Nov 21.

Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Azathioprine is a first-line drug used to maintain the remission of inflammatory bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 6-thioguanine nucleotides (6-TGN). There are large individual variations in the pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Read More

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

Genes (Basel) 2020 10 16;11(10). Epub 2020 Oct 16.

Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France.

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. Read More

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October 2020

Thiopurine -methyltransferase genetic polymorphisms in adult patients with inflammatory bowel diseases in the Latvian population.

Therap Adv Gastroenterol 2020 14;13:1756284820937426. Epub 2020 Jul 14.

Pauls Stradins Clinical University Hospital, Riga, Latvia.

Background: Thiopurine methyltransferase (TPMT) plays a significant role in the metabolism of thiopurines, and, for patients with inflammatory bowel disease (IBD), it is useful to perform TPMT genotyping prior to azathioprine (AZA) treatment. In this study, we determined gene polymorphisms in a cohort of IBD patients in Latvia.

Methods: DNA samples were obtained from 244 IBD patients, and qPCR was performed for detection of rs1800462, rs1800460, and rs1142345 single-nucleotide polymorphisms (SNPs). Read More

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Adjustment of azathioprine dose should be based on a lower 6-TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers.

Aliment Pharmacol Ther 2020 08 29;52(3):459-470. Epub 2020 Jun 29.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known.

Aim: To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels.

Methods: This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Read More

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Cost-effectiveness analysis of pretreatment screening for NUDT15 defective alleles.

Pharmacogenet Genomics 2020 10;30(8):175-183

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie.

Background: Nucleotide triphosphate diphosphatase (NUDT15) genetic testing in addition to thiopurine methyl transferase (TPMT) is recommended to reduce the incidence of adverse severe myelotoxicity episodes induced by thiopurines.

Objective: We assessed the cost-effectiveness ratio of combined screening for TMPT and NUDT15 defective alleles by genotyping or next-generation sequencing (NGS) using TPMT genotyping as the reference. Because of the genetic differences in thiopurine toxicity, we tested the screening strategies on individuals of Caucasian and Asian descent. Read More

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October 2020

Effects of various genetic polymorphisms on thiopurine treatment-associated outcomes for Korean patients with Crohn's disease.

Br J Clin Pharmacol 2020 11 1;86(11):2302-2313. Epub 2020 Jun 1.

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Aims: This study explores the effects of various genetic polymorphisms in candidate genes on thiopurine metabolism and toxicity in adult patients with Crohn's disease in Korea.

Methods: A total of 131 adult patients with Crohn's disease receiving thiopurine treatment were included. The TPMT and NUDT15 genes and an additional 116 genetic polymorphisms (in 40 genes and 3 intergenic locations) were screened for genotyping. Read More

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November 2020

Understanding the state of pharmacogenomic testing for thiopurine methyltransferase within a large health system.

Pharmacogenomics 2020 04 20;21(6):411-418. Epub 2020 Apr 20.

Duke Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA.

To investigate the current state of TPMT testing at a single-academic medical center. Single-center, retrospective chart review for patients newly prescribed a thiopurine. Data collection and evaluation included the prevalence and timing of TPMT testing, correct dosage adjustment if applicable, and incidence of myelosuppression. Read More

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Clinical Application of Thiopurine Pharmacogenomics in Pediatrics.

Curr Drug Metab 2020 ;21(1):53-62

Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.

Background: Thiopurine drugs are used for the treatment of pediatric diseases. Inter-individual differences in the metabolism of these drugs greatly influence the risk of thiopurine induced toxicity and therapy failure. These differences are the consequence of genomic, epigenomic and transcriptomic variability among patients. Read More

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PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients.

Pharmacogenomics J 2020 06 3;20(3):415-425. Epub 2019 Dec 3.

Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", Trieste, Italy.

The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0. Read More

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Reducing risk in thiopurine therapy.

Xenobiotica 2020 Jan 12;50(1):101-109. Epub 2019 Nov 12.

Purine Research Laboratory, Viapath, St Thomas' Hospital, London, UK.

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Read More

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January 2020

Severe pancytopenia and aspergillosis caused by thioguanine in a thiopurine S-methyltransferase deficient patient: a case report.

Eur J Gastroenterol Hepatol 2019 12;31(12):1592-1596

Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein.

Azathioprine and mercaptopurine are widely used in the treatment of inflammatory bowel disease. However, its use is limited by adverse drug event related to the relatively narrow therapeutic index of the active metabolites. Several patients discontinue treatment because of intolerable adverse events or toxicity such as leucopenia and hepatotoxicity. Read More

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December 2019

Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases.

Clin Gastroenterol Hepatol 2020 08 22;18(9):2010-2018.e2. Epub 2019 Aug 22.

Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background & Aims: Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments.

Methods: We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Read More

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Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients.

Medicina (Kaunas) 2019 Aug 5;55(8). Epub 2019 Aug 5.

Department of General and Specialist Medicine, Gastroenterologia-U, Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy.

In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Read More

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Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD.

Aliment Pharmacol Ther 2019 09 25;50(5):484-506. Epub 2019 Jul 25.

Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients.

Aim: To assess risk factors for thiopurine-induced leukopenia in IBD.

Methods: MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia. Read More

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September 2019

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

Dig Dis Sci 2019 09 9;64(9):2395-2403. Epub 2019 Jul 9.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. Read More

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September 2019

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants.

Genes (Basel) 2019 04 4;10(4). Epub 2019 Apr 4.

Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy.

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Read More

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Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis.

Mol Diagn Ther 2019 06;23(3):429-438

Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descates, 20, rue Leblanc, 75015, Paris, France.

Background: Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known.

Objective: Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine. Read More

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Combined evaluation of genotype and phenotype of thiopurine S-methyltransferase (TPMT) in the clinical management of patients in chronic therapy with azathioprine.

Drug Metab Pers Ther 2019 03 6;34(1). Epub 2019 Mar 6.

Department of Laboratory Medicine, ASST Niguarda Hospital, Milan, Italy.

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. Read More

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[Frequency of serious adverse events of thiopurine treatment in normal thiopurine S-methyltransferase genotype children with inflammatory bowel disease].

Authors:
András Tárnok

Orv Hetil 2019 Feb;160(5):179-185

Gyermekgyógyászati Klinika, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs, József A. u. 7., 7623.

Introduction: Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases. Read More

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February 2019