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1
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Qu YT, Ding JY, Pan W, Liu FR, Dong AL. Perspectives in clinical research on Azathioprine for steroid-dependent ulcerative colitis. Front Med (Lausanne) 2025; 12:1551906. [PMID: 40201324 PMCID: PMC11975918 DOI: 10.3389/fmed.2025.1551906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 03/11/2025] [Indexed: 04/10/2025] Open
Abstract
This study explores the application of Azathioprine in the treatment of ulcerative colitis (UC) and the challenges associated with its long-term use. While short-term studies demonstrate the efficacy of Azathioprine in steroid-dependent UC, long-term data on its risks, including malignancies, infections, and chronic toxicity, remain insufficient. Furthermore, the impact of Azathioprine on patients' quality of life over extended periods is still unclear. The research highlights the importance of optimizing Azathioprine dosing based on genomic data, particularly through TPMT and NUDT15 genotyping, to minimize adverse effects. However, further research is needed to develop individualized treatment strategies that can improve efficacy and reduce toxicity. The identification of predictive biomarkers, through genomics and proteomics, is likely to play a crucial role in improving treatment precision by identifying patients who are most likely to benefit from Azathioprine therapy. Additionally, combining Azathioprine with biologic therapies (such as anti-TNF agents or integrin inhibitors) and interventions targeting the gut microbiome may enhance the drug's effectiveness while reducing reliance on steroids. Overall, large-scale clinical trials are urgently needed to evaluate the benefits and risks of these emerging therapies, ultimately supporting more personalized treatment approaches for steroid-dependent UC patients.
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Affiliation(s)
- Yuan-Ting Qu
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Jia-Yuan Ding
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Wei Pan
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Fang-Rui Liu
- Department of Gastroenterology, Mudanjiang First People’s Hospital, Mudanjiang, China
| | - Ai-Lian Dong
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
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Dickson AL, Daniel LL, Zanussi J, Dale Plummer W, Wei WQ, Liu G, Reese T, Anandi P, Birdwell KA, Kawai V, Cox NJ, Dupont WD, Hung AM, Feng Q, Stein CM, Chung CP. TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real-World Clinical Results. Clin Pharmacol Ther 2022; 111:263-271. [PMID: 34582038 PMCID: PMC8678305 DOI: 10.1002/cpt.2428] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/20/2021] [Indexed: 01/03/2023]
Abstract
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. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.
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Affiliation(s)
- Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Laura L Daniel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jacy Zanussi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - W Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wei-Qi Wei
- Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ge Liu
- Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Tyler Reese
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Prathima Anandi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kelly A Birdwell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Vivian Kawai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Adriana M Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Tennessee Valley Healthcare System - Nashville Campus, Nashville, Tennessee, USA
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Tennessee Valley Healthcare System - Nashville Campus, Nashville, Tennessee, USA
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Bergan S, Brunet M, Hesselink DA, Johnson-Davis KL, Kunicki PK, Lemaitre F, Marquet P, Molinaro M, Noceti O, Pattanaik S, Pawinski T, Seger C, Shipkova M, Swen JJ, van Gelder T, Venkataramanan R, Wieland E, Woillard JB, Zwart TC, Barten MJ, Budde K, Dieterlen MT, Elens L, Haufroid V, Masuda S, Millan O, Mizuno T, Moes DJAR, Oellerich M, Picard N, Salzmann L, Tönshoff B, van Schaik RHN, Vethe NT, Vinks AA, Wallemacq P, Åsberg A, Langman LJ. Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2021; 43:150-200. [PMID: 33711005 DOI: 10.1097/ftd.0000000000000871] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
ABSTRACT When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
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Affiliation(s)
- Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Kamisha L Johnson-Davis
- Department of Pathology, University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Paweł K Kunicki
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | - Florian Lemaitre
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France
| | - Pierre Marquet
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Mariadelfina Molinaro
- Clinical and Experimental Pharmacokinetics Lab, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Ofelia Noceti
- National Center for Liver Tansplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | | | - Tomasz Pawinski
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | | | - Maria Shipkova
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eberhard Wieland
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jean-Baptiste Woillard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Tom C Zwart
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Markus J Barten
- Department of Cardiac- and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maja-Theresa Dieterlen
- Department of Cardiac Surgery, Heart Center, HELIOS Clinic, University Hospital Leipzig, Leipzig, Germany
| | - Laure Elens
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK) Research Group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique, UCLouvain and Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Satohiro Masuda
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk J A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Nicolas Picard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | | | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nils Tore Vethe
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Alexander A Vinks
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Pierre Wallemacq
- Clinical Chemistry Department, Cliniques Universitaires St Luc, Université Catholique de Louvain, LTAP, Brussels, Belgium
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet and Department of Pharmacy, University of Oslo, Oslo, Norway; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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4
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Kofuji S, Sasaki AT. GTP metabolic reprogramming by IMPDH2: unlocking cancer cells' fuelling mechanism. J Biochem 2021; 168:319-328. [PMID: 32702086 DOI: 10.1093/jb/mvaa085] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 07/16/2020] [Indexed: 12/15/2022] Open
Abstract
Growing cells increase multiple biosynthetic processes in response to the high metabolic demands needed to sustain proliferation. The even higher metabolic requirements in the setting of cancer provoke proportionately greater biosynthesis. Underappreciated key aspects of this increased metabolic demand are guanine nucleotides and adaptive mechanisms to regulate their concentration. Using the malignant brain tumour, glioblastoma, as a model, we have demonstrated that one of the rate-limiting enzymes for guanosine triphosphate (GTP) synthesis, inosine monophosphate dehydrogenase-2 (IMPDH2), is increased and IMPDH2 expression is necessary for the activation of de novo GTP biosynthesis. Moreover, increased IMPDH2 enhances RNA polymerase I and III transcription directly linking GTP metabolism to both anabolic capacity as well as nucleolar enlargement historically observed as associated with cancer. In this review, we will review in detail the basis of these new discoveries and, more generally, summarize the current knowledge on the role of GTP metabolism in cancer.
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Affiliation(s)
- Satoshi Kofuji
- Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Atsuo T Sasaki
- Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0508, USA.,Department of Cancer Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., OH 45267-0508, USA.,Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, 3113 Bellevue Ave, Cincinnati, OH 45267-0508, USA.,Institute for Advanced Biosciences, Keio University, Kakuganji 246-2, Mizukami, Tsuruoka City, Yamagata 997-0052, Japan
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5
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Anandi P, Dickson AL, Feng Q, Wei WQ, Dupont WD, Plummer D, Liu G, Octaria R, Barker KA, Kawai VK, Birdwell K, Cox NJ, Hung A, Stein CM, Chung CP. Combining clinical and candidate gene data into a risk score for azathioprine-associated leukopenia in routine clinical practice. THE PHARMACOGENOMICS JOURNAL 2020; 20:736-745. [PMID: 32054992 PMCID: PMC7426242 DOI: 10.1038/s41397-020-0163-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/22/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023]
Abstract
Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.
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Affiliation(s)
- Prathima Anandi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ge Liu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rany Octaria
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katherine A Barker
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Vivian K Kawai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kelly Birdwell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Adriana Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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6
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Daniel LL, Dickson AL, Chung CP. Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine. Clin Rheumatol 2020; 40:65-73. [PMID: 32617765 DOI: 10.1007/s10067-020-05258-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.
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Affiliation(s)
- Laura L Daniel
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Alyson L Dickson
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Cecilia P Chung
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA. .,Tennessee Valley Healthcare System-Nashville Campus (CPC), Nashville, TN, USA. .,Vanderbilt Genetics Institute, Vanderbilt University School of Medicine (CPC), Nashville, TN, USA.
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7
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Salvadori M, Tsalouchos A. Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy. World J Transplant 2020; 10:90-103. [PMID: 32864355 PMCID: PMC7428791 DOI: 10.5500/wjt.v10.i5.90] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/26/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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8
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Wilson L, Tuson S, Yang L, Loomes D. Real-World Use of Azathioprine Metabolites Changes Clinical Management of Inflammatory Bowel Disease. J Can Assoc Gastroenterol 2020; 4:101-109. [PMID: 34056527 PMCID: PMC8158651 DOI: 10.1093/jcag/gwaa005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background Thiopurines such as 6-mercaptopurine and azathioprine have complex metabolism, resulting in significant inter-individual differences in clinical efficacy and risk of drug toxicity, making conventional weight-based dosing inaccurate and potentially unsafe. Therapeutic drug monitoring (TDM) of thiopurine metabolites improves clinical outcomes through dose optimization and toxicity monitoring. Despite evidence for TDM, use is limited, due in part to test availability and awareness. The objectives of this study were twofold: (1) to investigate how thiopurine TDM impacts clinical management of IBD patients and (2) to evaluate proportion of patients outside therapeutic 6TGN levels or exhibiting signs of toxicity Methods Patients who received thiopurine TDM as part of routine care underwent chart review of demographics, disease activity, medication dosing, metabolite levels, and adverse events. Changes in clinical management following TDM were measured. Additionally, we conducted a retrospective review of clinical decision making blinded and unblinded to TDM result. Results A total of 92 IBD patients were included. Levels of 6TGN were therapeutic in 29% of patients. 6TGN levels correlated weakly with weight-based dosing (r2 = 0.057, P = 0.02). Adverse reactions were observed in 6.5%. TDM informed clinical management in 64%. Significantly more changes to clinical management occurred in those with active disease than in remission (73% versus 48%; P = 0.02) and in those on mono- versus combination therapy (48% versus 27.5%; P = 0.03). Conclusions TDM informs clinical decision making in over two-thirds of patients. The demonstrated poor efficacy of weight-based dosing and impact of TDM on clinical management contributes to the evidence supporting the need for greater availability and uptake of thiopurine TDM.
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Affiliation(s)
- Laura Wilson
- Division of Gastroenterology, Vancouver Island IBD Clinic, Victoria, British Columbia, Canada
| | - Stephanie Tuson
- Division of Gastroenterology, Vancouver Island IBD Clinic, Victoria, British Columbia, Canada
| | - Lufang Yang
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dustin Loomes
- Division of Gastroenterology, Vancouver Island IBD Clinic, Victoria, British Columbia, Canada.,Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Roberts RL, Wallace MC, Seinen ML, van Bodegraven AA, Krishnaprasad K, Jones GT, van Rij AM, Baird A, Lawrance IC, Prosser R, Bampton P, Grafton R, Simms LA, Studd C, Bell SJ, Kennedy MA, Halliwell J, Gearry RB, Radford-Smith G, Andrews JM, McHugh PC, Barclay ML. Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:2606-2612. [PMID: 29788244 DOI: 10.1093/ibd/izy163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. METHODS Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. RESULTS Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. CONCLUSIONS The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.
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Affiliation(s)
- Rebecca L Roberts
- Department of Surgical Sciences (Dunedin), University of Otago, Otago, New Zealand
| | - Mary C Wallace
- Department of Surgical Sciences (Dunedin), University of Otago, Otago, New Zealand
| | - Margien L Seinen
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands.,Department of Internal Medicine, Gastroenterology and Geriatrics, Atrium-ORBIS Medical Center, Heerlen-Sittard, the Netherlands
| | - Adriaan A van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands.,Department of Internal Medicine, Gastroenterology and Geriatrics, Atrium-ORBIS Medical Center, Heerlen-Sittard, the Netherlands
| | | | - Gregory T Jones
- Department of Surgical Sciences (Dunedin), University of Otago, Otago, New Zealand
| | - Andre M van Rij
- Department of Surgical Sciences (Dunedin), University of Otago, Otago, New Zealand
| | - Angela Baird
- Centre for Inflammatory Bowel Disease, Saint John of God Hospital, Subiaco, WA, Australia
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Disease, Saint John of God Hospital, Subiaco, WA, Australia.,Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, WA, Australia
| | - Ruth Prosser
- Flinders Medical Centre, Flinders University of South Australia, Bedford Park, South Australia, Australia
| | - Peter Bampton
- Flinders Medical Centre, Flinders University of South Australia, Bedford Park, South Australia, Australia
| | - Rachel Grafton
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Lisa A Simms
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Corrie Studd
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Sally J Bell
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Martin A Kennedy
- Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
| | - Jacob Halliwell
- Centre for Biomarker Research, School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - Richard B Gearry
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Graham Radford-Smith
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Jane M Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Patrick C McHugh
- Centre for Biomarker Research, School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - Murray L Barclay
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
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10
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Lim SZ, Chua EW. Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring. Front Pharmacol 2018; 9:1107. [PMID: 30349479 PMCID: PMC6186994 DOI: 10.3389/fphar.2018.01107] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022] Open
Abstract
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
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Affiliation(s)
| | - Eng Wee Chua
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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11
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Tsesmetzis N, Paulin CBJ, Rudd SG, Herold N. Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism. Cancers (Basel) 2018; 10:cancers10070240. [PMID: 30041457 PMCID: PMC6071274 DOI: 10.3390/cancers10070240] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 07/18/2018] [Accepted: 07/20/2018] [Indexed: 02/07/2023] Open
Abstract
Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.
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Affiliation(s)
- Nikolaos Tsesmetzis
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 77 Stockholm, Sweden.
| | - Cynthia B J Paulin
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden.
| | - Sean G Rudd
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden.
| | - Nikolas Herold
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 77 Stockholm, Sweden.
- Paediatric Oncology, Theme of Children's and Women's Health, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
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12
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McCune JS, Storer B, Thomas S, McKiernan J, Gupta R, Sandmaier BM. Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 2018; 24:1802-1807. [PMID: 29656138 DOI: 10.1016/j.bbmt.2018.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/03/2018] [Indexed: 01/18/2023]
Abstract
We evaluated inosine monophosphate dehydrogenase (IMPDH) 1 and IMPDH2 pharmacogenetics in 247 recipient-donor pairs after nonmyeloablative hematopoietic cell transplant (HCT). Patients were conditioned with total body irradiation + fludarabine and received grafts from related or unrelated donors (10% HLA mismatch), with postgraft immunosuppression of mycophenolate mofetil (MMF) with a calcineurin inhibitor. Recipient and donor IMPDH genotypes (rs11706052, rs2278294, rs2278293) were not associated with day 28 T cell chimerism, acute graft-versus-host disease (GVHD), disease relapse, cytomegalovirus reactivation, nonrelapse mortality, or overall survival. Recipient IMPDH1 rs2278293 genotype was associated with a lower incidence of chronic GVHD (hazard ratio, .72; P = .008) in nonmyeloablative HCT recipients. Additional studies are needed to confirm these results with the goal of identifying predictive biomarkers to MMF that lower GVHD.
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Affiliation(s)
- Jeannine S McCune
- School of Pharmacy, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Population Sciences, City of Hope, Duarte, California; Department of Hematology and HCT, City of Hope, Duarte, California.
| | - Barry Storer
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sushma Thomas
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jožefa McKiernan
- Department of Population Sciences, City of Hope, Duarte, California
| | - Rohan Gupta
- Department of Hematology and HCT, City of Hope, Duarte, California
| | - Brenda M Sandmaier
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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13
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Munnig-Schmidt E, Zhang M, Mulder CJ, Barclay ML. Late-onset Rise of 6-MMP Metabolites in IBD Patients on Azathioprine or Mercaptopurine. Inflamm Bowel Dis 2018. [PMID: 29522107 DOI: 10.1093/ibd/izx081] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%-20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications. METHODS The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed. RESULTS Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 × 108 red blood cells. No common factors were found to explain the late onset. CONCLUSIONS Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001.
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Affiliation(s)
- Erik Munnig-Schmidt
- Department of Gastroenterology, VU Medical Centre, Amsterdam, the Netherlands
| | - Mei Zhang
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Chris J Mulder
- Department of Gastroenterology, VU Medical Centre, Amsterdam, the Netherlands
| | - Murray L Barclay
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.,Departments of Gastroenterology and Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
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14
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Beringer A, Citterio-Quentin A, Otero RO, Gustin C, Clarke R, Salvi JP, Boulieu R. Determination of inosine 5'-monophosphate dehydrogenase activity in red blood cells of thiopurine-treated patients using HPLC. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1044-1045:194-199. [PMID: 28110955 DOI: 10.1016/j.jchromb.2017.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 12/30/2016] [Accepted: 01/05/2017] [Indexed: 01/25/2023]
Abstract
Thiopurine drugs are commonly used in immune diseases and to a lesser extent, in transplant rejection prophylaxis: however interindividual variability in drug response and in the occurrence of adverse events is observed. Genetic variation in thiopurine S-methyltransferase (TPMT) doesn't completely explain the occurrence of all adverse events and drug response variability. The potential implication of other enzymes involved in thiopurine metabolism, such as ITPA, has been investigated over the last decade but little data is available on inosine 5'-monophosphate dehydrogenase (IMPDH) in patients treated with thiopurine drugs. The authors reported a HPLC method to determine IMPDH activity in the red blood cells (RBCs) of thiopurine-treated patients. IMPDH activity was evaluated by enzymatic conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP). The XMP formed was analyzed on a Luna® NH2 stationary phase, a weak anion exchange phase that exhibits both ionic and hydrophobic properties. XMP was eluted below 15min. Intra-assay and inter-assay precisions were below 9% for RBCs supplemented with 2, 40 and 80μmol/L of XMP. IMPDH activity was measured in adults without thiopurine treatment as well as in adult and paediatric patients treated with thiopurines. A wide interindividual variability in IMPDH activity in RBCs was observed. No difference in IMPDH activity was found between untreated subjects and adult and paediatric patients on thiopurine therapy (median value 11.8, 7.9 and 7.7nmol XPM/g Hb/h respectively). The method described is useful in the determination of IMPDH phenotype from patients on thiopurine therapy and in the investigation of the potential relationship between IMPDH activity in RBCs and the occurrence of adverse events and drug response variability.
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Affiliation(s)
- Audrey Beringer
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France; Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacocinétique Clinique, Lyon, France
| | - Antony Citterio-Quentin
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France; Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacocinétique Clinique, Lyon, France
| | - Rebeca Obenza Otero
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France
| | - Clémence Gustin
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France; Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacocinétique Clinique, Lyon, France
| | - Rebecca Clarke
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France; School of Pharmacy and Pharmaceuticals Sciences, Trinity College Dublin, Dublin, Ireland
| | - Jean-Paul Salvi
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France
| | - Roselyne Boulieu
- Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament, Lyon, France; Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacocinétique Clinique, Lyon, France.
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15
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Pouché L, Stojanova J, Marquet P, Picard N. New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs. Pharmacogenomics 2016; 17:277-96. [PMID: 26799749 DOI: 10.2217/pgs.15.169] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. The aim of this review is to facilitate research related to the pharmacodynamics of the main immunosuppressive drugs used in solid organ transplantation. We elaborated a quality of evidence grading system based on a literature review and identified 'highly recommended', 'recommended' or 'potential' candidates for further research. It is likely that a number of additional rare variants might further explain drug response phenotypes in transplantation, and particularly the most severe ones. The advent of next-generation sequencing will help to identify those variants.
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Affiliation(s)
- Lucie Pouché
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France
| | - Jana Stojanova
- Laboratory of Chemical Carcinogenesis & Pharmacogenetics, University of Chile, Santiago, Chile
| | - Pierre Marquet
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France.,FHU SUPORT, 87000 Limoges, France
| | - Nicolas Picard
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France.,FHU SUPORT, 87000 Limoges, France
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16
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Hareedy MS, El Desoky ES, Woillard JB, Thabet RH, Ali AM, Marquet P, Picard N. Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients. Pharmacogenomics 2015; 16:1119-34. [PMID: 26237184 DOI: 10.2217/pgs.15.62] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. MATERIALS & METHODS Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt. RESULTS We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse. CONCLUSION Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.
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Affiliation(s)
- Mohammad Salem Hareedy
- Department of Pharmacology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt.,Inserm, UMR-850, Limoges, France
| | - Ehab S El Desoky
- Department of Pharmacology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt
| | - Jean-Baptiste Woillard
- Inserm, UMR-850, Limoges, France.,Department of Pharmacology, Toxicology & Pharmacovigilance, CHU Limoges, Limoges, France.,Faculty of Medicine, Laboratory of Medical Pharmacology, University of Limoges, Limoges, France
| | - Romany Helmy Thabet
- Department of Pharmacology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt
| | | | - Pierre Marquet
- Inserm, UMR-850, Limoges, France.,Department of Pharmacology, Toxicology & Pharmacovigilance, CHU Limoges, Limoges, France.,Faculty of Medicine, Laboratory of Medical Pharmacology, University of Limoges, Limoges, France
| | - Nicolas Picard
- Inserm, UMR-850, Limoges, France.,Department of Pharmacology, Toxicology & Pharmacovigilance, CHU Limoges, Limoges, France.,South Egypt Cancer Institute, Assiut University, Assiut, Egypt
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17
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Roberts RL, Barclay ML. Update on thiopurine pharmacogenetics in inflammatory bowel disease. Pharmacogenomics 2015; 16:891-903. [PMID: 26067482 DOI: 10.2217/pgs.15.29] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
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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Affiliation(s)
- Rebecca L Roberts
- Department of Surgical Sciences, Dunedin School of Medicine, PO Box 56, Dunedin, New Zealand
| | - Murray L Barclay
- Department of Medicine, University of Otago Christchurch, PO Box 4345, Christchurch, New Zealand.,Department of Gastroenterology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
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18
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Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers. THE PHARMACOGENOMICS JOURNAL 2015; 15:414-21. [DOI: 10.1038/tpj.2015.9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 01/15/2014] [Accepted: 01/28/2015] [Indexed: 12/23/2022]
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19
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Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine. Int J Mol Sci 2015; 16:4281-305. [PMID: 25690039 PMCID: PMC4346957 DOI: 10.3390/ijms16024281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/04/2015] [Accepted: 02/09/2015] [Indexed: 12/25/2022] Open
Abstract
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
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20
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Min MX, Weinberg DI, McCabe RP. Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use. J Clin Pharm Ther 2014; 39:107-11. [DOI: 10.1111/jcpt.12125] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 12/05/2013] [Indexed: 12/14/2022]
Affiliation(s)
- M. X. Min
- Abbott Northwestern Hospital; Minneapolis MN USA
| | | | - R. P. McCabe
- Minnesota Gastroenterology PA; Minneapolis MN USA
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21
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Wojtuszkiewicz A, Barcelos A, Dubbelman B, De Abreu R, Brouwer C, Bökkerink JP, de Haas V, de Groot-Kruseman H, Jansen G, Kaspers GL, Cloos J, Peters GJ. Assessment of mercaptopurine (6MP) metabolites and 6MP metabolic key-enzymes in childhood acute lymphoblastic leukemia. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2014; 33:422-433. [PMID: 24940700 DOI: 10.1080/15257770.2014.904519] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N=236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP--TGN and meTIN--showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.
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Seinen ML, van Asseldonk DP, de Boer NKH, Losekoot N, Smid K, Mulder CJJ, Bouma G, Peters GJ, van Bodegraven AA. The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study. J Crohns Colitis 2013; 7:812-819. [PMID: 23317929 DOI: 10.1016/j.crohns.2012.12.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 12/04/2012] [Accepted: 12/10/2012] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. METHODS A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. RESULTS Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001). CONCLUSION Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.
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Affiliation(s)
- M L Seinen
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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Gene expression and thiopurine metabolite profiling in inflammatory bowel disease - novel clues to drug targets and disease mechanisms? PLoS One 2013; 8:e56989. [PMID: 23437289 PMCID: PMC3578787 DOI: 10.1371/journal.pone.0056989] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 01/16/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND AIMS Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. METHODS Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0-14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. RESULTS Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn's disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes. CONCLUSIONS Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.
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Roberts RL, Barclay ML. Current relevance of pharmacogenetics in immunomodulation treatment for Crohn's disease. J Gastroenterol Hepatol 2012; 27:1546-54. [PMID: 22741564 DOI: 10.1111/j.1440-1746.2012.07220.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
No drug therapy is completely risk free, and the costs associated with non-response and adverse effects can exceed the cost of the therapy. The ultimate goal of pharmacogenetic research is to find robust genetic predictors of drug response that enable the development of prospective genetic tests to reliably identify patients at risk of non-response or of developing an adverse effect prior to the drug being prescribed. Currently, thiopurine S-methyltransferase (TPMT) deficiency is the only pharmacogenetic factor that is prospectively assessed before azathioprine or 6-mercaptopurine immunomodulation is commenced in patients with Crohn's disease (CD). As yet no other inherited determinant of drug response has made the transition from bench to bedside for the management of this disease. In this review we summarize what is known about TPMT deficiency and explore whether there is evidence to support a role of other genetic polymorphisms in predicting the response of CD patients to thiopurine drugs, methotrexate, and anti-tumor necrosis factor α (TNFα) therapy.
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Affiliation(s)
- Rebecca L Roberts
- Department of Surgical Sciences, Dunedin School of Medicine, Dunedin, New Zealand.
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Blaker PA, Arenas-Hernandez M, Marinaki AM, Sanderson JD. The pharmacogenetic basis of individual variation in thiopurine metabolism. Per Med 2012; 9:707-725. [DOI: 10.2217/pme.12.85] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.
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Affiliation(s)
- Paul Andrew Blaker
- Department of Gastroenterology, 1st Floor College House, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, London, UK
| | - Monica Arenas-Hernandez
- The Purine Research Laboratory, Guy’s & St Thomas’ Hospitals NHS Foundation Trust , London, UK
| | - Anthony Marin Marinaki
- The Purine Research Laboratory, Guy’s & St Thomas’ Hospitals NHS Foundation Trust , London, UK
| | - Jeremy David Sanderson
- Department of Gastroenterology, 1st Floor College House, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, London, UK
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Kennedy MA, Joyce PR, Begg EJ. Institutional Profile: The Carney Centre for Pharmacogenomics: a New Zealand focus for personalized medicine research. Pharmacogenomics 2012; 13:865-8. [DOI: 10.2217/pgs.12.55] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The integration of genetics and genomics with pharmacology and clinical medicine has enriched our understanding of all of these disciplines and is steadily providing a more complete picture of the etiology, pathophysiology and treatment of disease. To capitalize on this new knowledge requires the ability to evaluate the underlying evidence base and to test the utility of any proposed pharmacogenetic or genomic approaches to personalized medicine, within local or regional healthcare structures. The Carney Centre for Pharmacogenomics is now in its eighth year of operation, and although small by international standards, it has proven to be a valuable focus for research, training and dissemination of such knowledge in New Zealand and beyond. By focusing predominantly on research and training, the center has raised awareness about the value and limitations of pharmacogenetics and pharmacogenomic approaches.
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Affiliation(s)
- Martin A Kennedy
- Carney Centre for Pharmacogenomics & Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand
| | - Peter R Joyce
- Department of Psychological Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand
| | - Evan J Begg
- Carney Centre for Pharmacogenomics & Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand
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van Egmond R, Chin P, Zhang M, Sies CW, Barclay ML. High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment. Aliment Pharmacol Ther 2012; 35:1181-9. [PMID: 22486532 DOI: 10.1111/j.1365-2036.2012.05084.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 12/07/2011] [Accepted: 03/13/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity. AIM To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT). METHODS The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups. RESULTS Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20. CONCLUSIONS In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP.
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Affiliation(s)
- R van Egmond
- Department of Clinical Pharmacology, Department of Gastroenterology, Christchurch Hospital, New Zealand
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Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 2012; 68:1233-42. [PMID: 22421815 DOI: 10.1007/s00228-012-1251-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Accepted: 02/14/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability. AIM This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.
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Evidence for a functional genetic polymorphism of the Rho-GTPase Rac1. Implication in azathioprine response? Pharmacogenet Genomics 2011; 21:313-24. [PMID: 21372752 DOI: 10.1097/fpc.0b013e3283449200] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Adverse effects of thiopurine drugs occur in 15-28% of patients and the majority is not explained by thiopurine-S-methyltransferase deficiency. Furthermore, approximately 9% of patients with inflammatory bowel disease are resistant to azathioprine therapy. Recently, the small guanosine triphosphatase, Rac1, was identified as an important molecular target of 6-thioguanine triphosphate, one of the active metabolite of thiopurines such as azathioprine. To date, no functional genetic polymorphism of the human Rac1 gene had been reported. OBJECTIVES Evidence for functional genetic polymorphisms of the human Rac1 gene and to investigate their relative contribution to the development of toxicity induced by azathioprine treatment in patients with inflammatory bowel disease. METHODS We first screened for polymorphisms in the Rac1 gene in genomic DNA samples from 92 unrelated Caucasian individuals. The functional consequences of identified polymorphisms were assessed in vitro using transient transfection assays in Jurkat and A549 cell lines. The relationship between polymorphisms of Rac1 and thiopurine response or hematotoxicity was studied in 128 patients under thiopurine treatment. RESULTS Three single nucleotide polymorphism and one variable number tandem repeat were identified in the promoter region of Rac1 gene. Interestingly, in Jurkat T cells, the c.-289G>C substitution and c.-283_-297[3] variable number tandem repeat displayed a significantly increased promoter activity (P<0.01) of 150 and 300%, respectively, compared with that of the wild-type sequence. Patients with thiopurine-S-methyltransferase mutations presented a significantly increased probability of developing hematotoxicity (odds ratio=5.68, 95% confidence interval=1.45-22.23, P=0.00625). Moreover, among the 75 patients who did not develop hematotoxicity, there was a marginally overrepresentation of functional genetic polymorphisms of Rac1 (odds ratio=0.18, 95% confidence interval=0.02-1.49, P=0.079). CONCLUSION This study constitutes the first report of a functional genetic polymorphism that could affect Rac1 expression and thus modulate the risk of adverse drug reaction in patients under thiopurine treatment. A larger scale (case-control) study should enable us to confirm or cancel these preliminary results.
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Roberts RL, Gearry RB, Barclay ML. Allopurinol-thiopurine combination therapy in inflammatory bowel disease: are there genetic clues to this puzzle? Pharmacogenomics 2011; 11:1505-8. [PMID: 21121769 DOI: 10.2217/pgs.10.143] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Gardiner SJ, Gearry RB, Burt MJ, Chalmers-Watson T, Chapman BA, Ross AG, Stedman CAM, Huelsen A, Barclay ML. Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio. J Gastroenterol Hepatol 2011; 26:49-54. [PMID: 21175793 DOI: 10.1111/j.1440-1746.2010.06489.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. METHODS Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. RESULTS The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. CONCLUSIONS In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.
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Affiliation(s)
- Sharon J Gardiner
- Department of Medicine, University of Otago, Christchurch, New Zealand
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Abstract
IMPORTANCE OF THE FIELD traditional immunosuppressants, including azathioprine, remain the mainstay of therapy in steroid dependent/refractory patients with inflammatory bowel diseases (IBD). The main limitations of its use are its side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity. Major complications occur in patients with low thiopurine-S-methyltransferase (TPMT) enzyme activity; however, the clinical relevance of these tests remains conflictive. AREAS COVERED IN THIS REVIEW in this review, the authors aim to summarize the new data regarding the relationship between the pharmacology of thiopurines and pathogenesis of adverse events. WHAT THE READER WILL GAIN readers will gain an understanding of the metabolism of thiopurines, side effect profile, pharmacological background of side effects, importance of metabolite monitoring, clinical relevance of inherited differences in drug metabolism and other conditions (e.g., concomitant use of allopurinol) which can modify enzyme activity. By gaining an understanding of the pharmacology and metabolism of thiopurines, clinicians will be able to optimize thiopurine therapy in IBD. TAKE HOME MESSAGE TPMT testing and metabolite monitoring are still not considered the standard of care, and clinicians will continue to choose the approach that best suits their clinical practice and patient needs. Regardless of what strategy is chosen, patients need to be carefully monitored and well informed about the potential risks.
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Affiliation(s)
- Pal Miheller
- Semmelweis University, 2nd Department of Medicine, Budapest, Koranyi, Hungary
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34
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Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol 2010; 63:288-95. [PMID: 20354201 DOI: 10.1136/jcp.2009.069252] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs. Patients that due to genetic variation lack this enzyme or have lower levels than normal, can be adversely affected if normal doses of thiopurines are prescribed. The evidence for measuring TPMT prior to starting patients on thiopurine drug therapy has been reviewed and the various approaches to establishing a service considered. Until recently clinical guidelines on the use of the TPMT varied by medical specialty. This has now changed, with clear guidance encouraging clinicians to use the TPMT test prior to starting any patient on thiopurine therapy. The TPMT test is the first pharmacogenomic test that has crossed from research to routine use. Several analytical approaches can be taken to assess TPMT status. The use of phenotyping supported with genotyping on selected samples has emerged as the analytical model that has enabled national referral services to be developed to a high level in the UK. The National Health Service now has access to cost-effective and timely TPMT assay services, with two laboratories undertaking the majority of the work at national level and with several local services developing. There appears to be adequate capacity and an appropriate internal market to ensure that TPMT assay services are commensurate with the clinical demand.
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Affiliation(s)
- L T Ford
- Clinical Biochemistry Department, SWBH NHS Trust, City Hospital, Dudley Road, Birmingham B18 5HQ, UK
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Smith MA, Marinaki AM, Sanderson JD. Pharmacogenomics in the treatment of inflammatory bowel disease. Pharmacogenomics 2010; 11:421-37. [PMID: 20235796 DOI: 10.2217/pgs.10.4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.
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Affiliation(s)
- Melissa A Smith
- Department of Gastroenterology, 1st Floor, College House, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK
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Kagaya H, Miura M, Saito M, Habuchi T, Satoh S. Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation. Basic Clin Pharmacol Toxicol 2010; 107:631-6. [PMID: 20136638 DOI: 10.1111/j.1742-7843.2010.00542.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5'-monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post-transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (p = 0.243 and 0.735, respectively). However, in the high MPA night-time exposure range (AUC > 60 microg x h/ml and C(0 )> or = 1.9 microg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each p = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.
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Affiliation(s)
- Hideaki Kagaya
- Department of Pharmacy, Akita University Hospital, Akita, Japan
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Fotoohi AK, Coulthard SA, Albertioni F. Thiopurines: factors influencing toxicity and response. Biochem Pharmacol 2010; 79:1211-20. [PMID: 20096268 DOI: 10.1016/j.bcp.2010.01.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Revised: 12/22/2009] [Accepted: 01/12/2010] [Indexed: 11/17/2022]
Abstract
Thiopurines are the backbone of current anti-leukemia regimens and have also been effective immunosuppressive agents for the past half a century. Extensive research on their mechanism of action has been undertaken, yet many issues remain to be addressed to resolve unexplained cases of thiopurine toxicity or treatment failure. The aim of this review is to summarize current knowledge of the mechanism of thiopurine action in experimental models and put into context with clinical observations. Clear understanding of their metabolism will contribute to maximizing efficacy and minimizing toxicity by individually tailoring therapy according to the expression profile of relevant factors involved in thiopurine activation pathway.
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Affiliation(s)
- Alan Kambiz Fotoohi
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden
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38
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Smith MA, Marinaki AM, Arenas M, Shobowale-Bakre M, Lewis CM, Ansari A, Duley J, Sanderson JD. Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Aliment Pharmacol Ther 2009; 30:375-84. [PMID: 19500084 DOI: 10.1111/j.1365-2036.2009.04057.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Azathioprine (AZA) pharmacogenetics are complex and much studied. Genetic polymorphism in TPMT is known to influence treatment outcome. Xanthine oxidase/dehydrogenase (XDH) and aldehyde oxidase (AO) compete with TPMT to inactivate AZA. AIM To assess whether genetic polymorphism in AOX1, XDH and MOCOS (the product of which activates the essential cofactor for AO and XDH) is associated with AZA treatment outcome in IBD. METHODS Real-time PCR was conducted for a panel of single nucleotide polymorphism (SNPs) in AOX1, XDH and MOCOS using TaqMan SNP genotyping assays in a prospective cohort of 192 patients receiving AZA for IBD. RESULTS Single nucleotide polymorphism AOX1 c.3404A > G (Asn1135Ser, rs55754655) predicted lack of AZA response (P = 0.035, OR 2.54, 95%CI 1.06-6.13) and when combined with TPMT activity, this information allowed stratification of a patient's chance of AZA response, ranging from 86% in patients where both markers were favourable to 33% where they were unfavourable (P < 0.0001). We also demonstrated a weak protective effect against adverse drug reactions (ADRs) from SNPs XDH c.837C > T (P = 0.048, OR 0.23, 95% CI 0.05-1.05) and MOCOS c.2107A > C, (P = 0.058 in recessive model, OR 0.64, 95%CI 0.36-1.15), which was stronger where they coincided (P = 0.019). CONCLUSION These findings have important implications for clinical practice and our understanding of AZA metabolism.
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Affiliation(s)
- M A Smith
- Department of Gastroenterology, Guy's & St. Thomas' NHS Foundation Trust, London, UK
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Gardiner SJ, Gearry RB, Burt MJ, Ding SL, Barclay ML. Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides. Eur J Gastroenterol Hepatol 2008; 20:1238-42. [PMID: 18989148 DOI: 10.1097/meg.0b013e3282ffda37] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Azathioprine and its initial metabolite, 6-mercaptopurine (6-MP), are associated with high rates of treatment cessation due to toxicity or inadequate response. Individualization of thiopurine dose based on concentrations of the active 6-thioguanine nucleotide (6-TGN) metabolites can help improve outcomes with this class. Some individuals, however, preferentially metabolize thiopurine drugs to the potentially hepatotoxic 6-methylmercaptopurine nucleotide (6-MMPN) metabolites rather than the 6-TGNs. For these patients, escalation in thiopurine dose is not likely to increase 6-TGN concentrations sufficiently but may lead to a disproportionate increase in exposure to the 6-MMPNs. We present three cases in whom thiopurine dose escalation based on clinical status and low 6-TGN concentrations (100-262 pmol/8 x 10 RBC) resulted in severe hepatotoxicity (liver failure in two cases) associated with unrecognized extremely high 6-MMPN concentrations of 26,000-40,000 pmol/8 x 10 RBC. These cases illustrate a risk with thiopurine dose adjustment based on monitoring of 6-TGN metabolites without also monitoring 6-MMPN.
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Affiliation(s)
- Sharon J Gardiner
- Department of Clinical Pharmacology, Christchurch Hospital, University of Otago, Christchurch, New Zealand
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40
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Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, Oussalah A, Seddik M, Canva V, Cortot A, Sogni P, Gueant JL, Bigard MA, Roblin X, Bronowicki JP. Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression. Aliment Pharmacol Ther 2008; 28:984-93. [PMID: 18657132 DOI: 10.1111/j.1365-2036.2008.03812.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The interaction of ribavirin, an inosine monophosphate dehydrogenase inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity, remains unexplored. AIM To underline the interaction of ribavirin, an inosine monophosphate dehydrogenase inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity. METHODS The medical records of eight patients who developed severe pancytopenia following concomitant use of azathioprine and ribavirin were retrospectively reviewed. RESULTS Bone marrow suppression reached nadir after a mean interval of 4.6 +/- 1.6 weeks following HCV therapy initiation in seven patients. At the time of pancytopenia, the mean platelet count was 69.75 +/- 82.8 x 10(-3)/mm(3), mean haemoglobin level 7.75 +/- 1.3 g/dL and mean neutrophil count 0.45 +/- 0.26 x 10(-3)/mm(3). All patients had normal thiopurine methyltransferase genotype. In two patients, a prospective monitoring of azathioprine metabolites was available. Myelotoxicity was accompanied by elevated total methylated metabolite levels (16,500 and 15,000 pmol/8 x 10(8) erythrocytes) with a concomitant decrease in 6-tioguanine nucleotide levels; 1 month after azathioprine, pegylated interferon alfa and ribavirin were discontinued and full blood count returned to normal in both patients. No haematological toxicity occurred after the reintroduction of peginterferon plus ribarivin or azathioprine alone in eight patients. CONCLUSION Collectively, the benefit/risk ratio favours avoidance of inosine monophosphate dehydrogenase inhibitors in purine analogue-treated patients with normal thiopurine methyltransferase activity, a situation frequently encountered in clinical practice.
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Affiliation(s)
- L Peyrin-Biroulet
- INSERM, U724, and Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-les-Nancy, France
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41
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Andoh A, Tsujikawa T, Ban H, Hashimoto T, Bamba S, Ogawa A, Sasaki M, Saito Y, Fujiyama Y. Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2008; 23:1373-7. [PMID: 18662197 DOI: 10.1111/j.1440-1746.2008.05419.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients. METHODS Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography. RESULTS The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations. CONCLUSION The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.
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Affiliation(s)
- Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Seta Tukinowa, Japan.
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Roberts RL, Gearry RB, Kennedy MA, Barclay ML. Beyond TPMT: genetic influences on thiopurine drug responses in inflammatory bowel disease. Per Med 2008; 5:233-248. [PMID: 29783500 DOI: 10.2217/17410541.5.3.233] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Azathioprine and 6-mercaptopurine are widely used in the management of inflammatory bowel disease (IBD). However, approximately 25% of IBD patients experience toxicity, and up to 10% show resistance to these thiopurine drugs. The importance of genetic variability in determining thiopurine toxicity was first recognized over 25 years ago with the discovery of the thiopurine S-methyltransferase (TPMT) polymorphism and the occurrence of azathioprine-induced myelosuppression in TPMT-deficient patients. In the intervening period, TPMT has become the foremost example of pharmacogenetics, and TPMT deficiency represents one of the few pharmacogenetic phenomena that have successfully made the transition from the research laboratory to diagnostics. While TPMT activity predicts some cases of myelosuppression, deficiency in this enzyme is neither predictive of other adverse drug reactions, nor resistance to thiopurine therapy. As myelosuppression only accounts for approximately 2.5% of adverse reactions in IBD patients, researchers are increasingly turning their attention to other enzymes involved in thiopurine metabolism to find molecular explanations for intolerance and resistance to azathioprine and 6-mercaptopurine. In this review, we summarize the current state of knowledge with regards to TPMT, and also explore genetic variability, beyond TPMT, that may contribute to thiopurine response in IBD patients.
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Affiliation(s)
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch 8140, New Zealand.,Department of Gastroenterology, Christchurch Hospital, Private Bag 151, Christchurch 8140, New Zealand
| | - Martin A Kennedy
- Department of Pathology, University of Otago, Christchurch 8140, New Zealand
| | - Murray L Barclay
- Department of Medicine, University of Otago, Christchurch 8140, New Zealand.,Department of Gastroenterology, Christchurch Hospital, Private Bag 151, Christchurch 8140, New Zealand
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Haglund S, Taipalensuu J, Peterson C, Almer S. IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol 2007; 65:69-77. [PMID: 17662091 PMCID: PMC2291267 DOI: 10.1111/j.1365-2125.2007.02985.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
AIMS Azathioprine and 6-mercaptopurine are steroid-sparing drugs used in inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and occurrence of adverse events. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the role of inosine-5'-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo synthesis of guanine nucleotides and also strategically positioned in the metabolic pathway of thiopurines. METHODS IMPDH was measured in 100 healthy blood donors. IMPDH, TPMT and metabolite concentrations were studied in 50 patients with IBD on stable thiopurine therapy. IMPDH activity was measured in peripheral blood mononuclear cells. TPMT activity, 6-methylthioinosine 5'-monophosphate (meTIMP) and 6-thioguanine nucleotide (6-TGN) concentrations were measured in red blood cells, which is the current practice in clinical monitoring of thiopurines. Enzyme activities were related to metabolite concentrations and clinical characteristics. RESULTS A wide range of IMPDH activity was observed both in healthy blood donors (median 13.1, range 4.7-24.2 nmol mg(-1) protein h(-1)) and IBD patients (median 14.0, range 7.0-21.7). There was a negative correlation between IMPDH activity and dose-normalized meTIMP concentrations (r(s) = -0.31, P = 0.03), but no evident correlation to 6-TGN concentration or the meTIMP/6-TGN ratio. There were no significant correlations between TPMT activity and metabolite concentrations. CONCLUSION Even though the meTIMP concentrations correlated inversely to the IMPDH activity, the role of IMPDH in balancing the formation of methylated and phosphorylated metabolites was not evident. Taken together, the results give cause to question established opinions about thiopurine metabolism.
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Affiliation(s)
- Sofie Haglund
- Research and Development in Laboratory Medicine, Laboratory Medicine, Ryhov Hospital, Linköping, Sweden.
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