{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:53:42Z","timestamp":1773856422325,"version":"3.50.1"},"reference-count":121,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T00:00:00Z","timestamp":1594598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grupo de Estudos de Doen\u00e7a Inflamat\u00f3ria Intestinal","award":["Investigation Scholarship 2018"],"award-info":[{"award-number":["Investigation Scholarship 2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines\u2019 metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines\u2019 metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol\/8 \u00d7 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol\/8 \u00d7 108 RBC), and lower in patients with hepatotoxicity (MD \u221240.6 pmol \u00d7 108 RBC). We established a significant correlation between 6-TGN and leukocytes (r = \u22120.21), neutrophils (r = \u22120.24) and alanine aminotransferase levels (r = \u22120.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95% CI 2.24; 9.57). An optimal cut-off of 135 pmol\/8 \u00d7 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol\/8 \u00d7 108 RBC; OR 4.28; 95% CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines\u2019 toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.<\/jats:p>","DOI":"10.3390\/jcm9072216","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T11:03:23Z","timestamp":1594724603000},"page":"2216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Thiopurines\u2019 Metabolites and Drug Toxicity: A Meta-Analysis"],"prefix":"10.3390","volume":"9","author":[{"given":"Paula","family":"Sousa","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Viseu Unit, Tondela-Viseu Hospital Centre, 3504-509 Viseu, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7171-0139","authenticated-orcid":false,"given":"Maria Manuela","family":"Estevinho","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of Porto, 4200-450 Porto, Portugal"},{"name":"Department of Gastroenterology, Centro Hospitalar Vila Nova de Gaia\/Espinho, 4434-502 Vila Nova de Gaia, Portugal"}]},{"given":"Cl\u00e1udia Camila","family":"Dias","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Information and Decision in Health, University of Porto, 4200-450 Porto, Portugal"},{"name":"Centre for Health Technology and Services Research, University of Porto, 4200-450 Porto, Portugal"}]},{"given":"Paula","family":"Ministro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Viseu Unit, Tondela-Viseu Hospital Centre, 3504-509 Viseu, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7156-0588","authenticated-orcid":false,"given":"Uri","family":"Kopylov","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Sheba Medical Central, Ramat Gan and Sackler Medical School, Tel Aviv University, 52621 Ramat Gan, Israel"}]},{"given":"Silvio","family":"Danese","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy"},{"name":"Humanitas Clinical and Research Center, IRCCS, 20089 Milan, Italy"}]},{"given":"Laurent","family":"Peyrin-Biroulet","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandoeuvre-l\u00e8s-Nancy, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9668","authenticated-orcid":false,"given":"Fernando","family":"Magro","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of Porto, 4200-450 Porto, Portugal"},{"name":"Department of Gastroenterology, S\u00e3o Jo\u00e3o University Hospital, 4200-319 Porto, Portugal"},{"name":"MedInUP, Centre for Drug Discovery and Innovative Medicines, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"981","DOI":"10.2174\/138920009790711887","article-title":"On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance","volume":"10","author":"Peters","year":"2009","journal-title":"Curr. 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