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Bayoumy AB, D'Agnolo HMA, de Boer NKH, Mulder CJJ, Derijks LJJ. The fate of thiopurine metabolites after switching to low-dose thiopurine with allopurinol or thioguanine in IBD patients: A retrospective analysis. Br J Clin Pharmacol 2025. [PMID: 40421668 DOI: 10.1002/bcp.70112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/28/2025] Open
Abstract
AIMS Shunting (hypermethylating) thiopurine metabolism, characterized by excessive 6-MMPR production and (sub)therapeutic 6-TGN levels, poses a significant challenge in the treatment of inflammatory bowel disease (IBD). This study evaluates the metabolic outcomes of switching to low-dose thiopurine with allopurinol (LDTA) or thioguanine (TG) in IBD patients with shunting metabolism. METHODS This retrospective study analysed demographic data, thiopurine metabolite profiles, and adverse event rates in shunting IBD patients before and after switching to LDTA or TG therapy. Metabolite variability was assessed by examining alterations in 6-MMPR and 6-TGN levels and their correlation before and after therapy switch. RESULTS Both therapies significantly reduced toxic 6-MMPR levels, with 100% of patients achieving non-toxic levels (6-MMPR-level below 7000 pmol/8 × 10E8 RBC) post-therapy. For TG, 93% of patients attained non-toxic 6-TGN levels (6-TGN < 1000 pmol/8 × 10E8 RBC). In contrast, LDTA showed greater variability in 6-TGN outcomes, with 50% of patients reaching therapeutic levels, 31% remaining subtherapeutic, and 19% within toxic range. The slope for LDTA was significantly positive (1.044, R2 = 0.4515, P = 0.004), reflecting proportional increases in 6-TGN levels. CONCLUSIONS Switching to LDTA or TG therapy in shunting IBD patients resulted in favourable alterations in thiopurine metabolism. However, LDTA appears to have a slightly less favourable metabolite profile, with some residual 6-MMPR formation and fewer patients achieving normal 6-TGN levels compared to TG. Given the challenges associated with achieving optimal thiopurine metabolite levels with LDTA and the need for closer monitoring of 6-TGN levels, TG appears a more suitable option for thiopurine shunting IBD patients.
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Affiliation(s)
- Ahmed B Bayoumy
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, The Netherlands
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, Veldhoven, The Netherlands
| | - Hedwig M A D'Agnolo
- Department of Gastroenterology and Hepatology, Máxima Medical Center, Veldhoven, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, The Netherlands
| | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, The Netherlands
| | - Luc J J Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, Veldhoven, The Netherlands
- Department of Clinical Pharmacy and Toxicology and NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
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Carlsson B, Karlsson L, Ärlemalm A, Sund S, Appell ML. Quantification of deoxythioguanosine in human DNA with LC-MS/MS, a marker for thiopurine therapy optimisation. Anal Bioanal Chem 2024; 416:6711-6723. [PMID: 39397163 PMCID: PMC11579148 DOI: 10.1007/s00216-024-05581-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/15/2024]
Abstract
In the treatment of diseases such as acute childhood leukaemia (ALL) and inflammatory bowel disease (IBD), the thiopurines azathioprine, 6-mercaptopurine, and 6-thioguanine are used. Thiopurines are antimetabolites and immunomodulators used to maintain remission in patients. They are all prodrugs and must be converted into the competing antimetabolites thioguanosine triphosphate and deoxythioguanosine triphosphate for final incorporation into RNA or DNA. The current therapeutic drug monitoring (TDM) method measures the sum of the formed metabolites in the sample, after acidic hydrolysis at high temperature. In this work, the goal is to measure these drugs closer to their pharmacological endpoints, once incorporated into DNA. After extracting DNA from whole blood, followed by DNA hydrolysis, 2'-deoxythioguanosine (dTG) and the complementary natural nucleobase 2'-deoxycytidine (dC) were measured. Chromatographic separation on a HSS T3 column followed by mass spectrometric detection was performed in multi-reaction monitoring (MRM) mode on a Xevo TQ-XS with ESI in positive mode, within 5 min. The concentration range for dTG was 0.04-5 nmol/L, and for dC, 0.1-12.5 µmol/L. The lower limit of detection was determined to a concentration of 0.003 nmol/L for dTG and 0.019 µmol/L for dC. The intra- and inter-assay imprecision for the quality controls ranged between 3.0 and 5.1% and between 8.4 and 10.9%, respectively. Sample stability for up to 4 years is shown. In summary, a sensitive method to quantify the thiopurines incorporated into DNA as dTG has been developed and will be used in further clinical studies for a better understanding of the mode of action of the thiopurines and the use of this method in TDM.
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Affiliation(s)
- Björn Carlsson
- Department of Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
| | - Louise Karlsson
- Department of Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Andreas Ärlemalm
- Department of Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Sophie Sund
- Department of Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Gargallo-Puyuelo CJ, Laredo V, Gomollón F. Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era? Front Med (Lausanne) 2021; 8:681907. [PMID: 34336887 PMCID: PMC8322650 DOI: 10.3389/fmed.2021.681907] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/23/2021] [Indexed: 12/18/2022] Open
Abstract
Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.
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Affiliation(s)
| | - Viviana Laredo
- Department of Gastroenterology, University Clinic Hospital Lozano Blesa, Zaragoza, Spain
| | - Fernando Gomollón
- Department of Gastroenterology, University Clinic Hospital Lozano Blesa, Zaragoza, Spain.,Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Zaragoza, Spain.,Institute for Health Research Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas, Madrid, Spain
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Selvi SV, Nataraj N, Chen SM, Prasannan A. An electrochemical platform for the selective detection of azathioprine utilizing a screen-printed carbon electrode modified with manganese oxide/reduced graphene oxide. NEW J CHEM 2021. [DOI: 10.1039/d0nj05592a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Scheme representing the electro-reduction of AZT at Mn2O3–rGO/SPCE.
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Affiliation(s)
- Subash Vetri Selvi
- Electroanalysis and Bioelectrochemistry Lab
- Department of Chemical Engineering and Biotechnology
- National Taipei University of Technology
- Taipei 106
- Republic of China
| | - Nandini Nataraj
- Electroanalysis and Bioelectrochemistry Lab
- Department of Chemical Engineering and Biotechnology
- National Taipei University of Technology
- Taipei 106
- Republic of China
| | - Shen-Ming Chen
- Electroanalysis and Bioelectrochemistry Lab
- Department of Chemical Engineering and Biotechnology
- National Taipei University of Technology
- Taipei 106
- Republic of China
| | - Adhimoorthy Prasannan
- Department of Materials Science and Engineering
- National Taiwan University of Science and Technology
- Taipei 10607
- Republic of China
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Zhu X, Chao K, Li M, Xie W, Zheng H, Zhang JX, Hu PJ, Huang M, Gao X, Wang XD. Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients. World J Gastroenterol 2019; 25:5850-5861. [PMID: 31636477 PMCID: PMC6801191 DOI: 10.3748/wjg.v25.i38.5850] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?
AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.
METHODS Patients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.
RESULTS A total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.
CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
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Affiliation(s)
- Xia Zhu
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Kang Chao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Miao Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States
| | - Hong Zheng
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Jin-Xin Zhang
- School of Public Health, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Pin-Jin Hu
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiang Gao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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Sánchez Rodríguez E, Ríos León R, Mesonero Gismero F, Albillos A, Lopez-Sanroman A. Clinical experience of optimising thiopurine use through metabolite measurement in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:629-635. [PMID: 30107940 DOI: 10.1016/j.gastrohep.2018.06.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites. PATIENTS AND METHODS Retrospective analysis on a prospective database of 31 patients with inflammatory bowel disease who failed therapy with thiopurines. Thiopurine metabolites (6-thioguanine, 6-TGN and 6-methylmercaptopurine, 6-MMP) were measured by high-performance liquid chromatography (Laboratorios Cerba, Barcelona) and treatment was duly adjusted in accordance with the results. Clinical response was reassessed after six months. RESULT Despite the appropriate theoretical dose of thiopurines being administered, the dose was insufficient in 45.6% of patients (nonadherence to treatment suspected in 6.45%) and 16.2% received an excessive dose or the drug was metabolised by other metabolic pathways. After treatment was optimised based on metabolite levels, only 25.8% (8/31) were prescribed a biological agent, while 74.2% of cases (23/31) were managed through dose optimisation alone. DISCUSSION Monitoring thiopurine metabolite levels may help clinicians to assess non-responsive patients before adding or switching to another drug (generally a biological agent), thereby avoiding any additional costs or potential toxicity. This strategy may also help to identify patients receiving an insufficient dose and those with an alternative metabolic pathway, who could be candidates for low-dose AZA with allopurinol, as well as patients who are suspected of being non-adherent. In three out of four patients, switching to a biological agent can be avoided.
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Affiliation(s)
| | - Raquel Ríos León
- Servicio de Gastroenterología y Hepatología, Hospital Ramón y Cajal, Madrid, España
| | | | - Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Ramón y Cajal, Madrid, España
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