Thiopurines’ metabolites and drug toxicity: A meta analysis

Paula Sousa, Maria Manuela Estevinho, Cláudia Camila Dias, Paula Ministro, Uri Kopylov, Silvio Danese, Laurent Peyrinbiroulet, Fernando Magro

Research output: Contribution to journalReview articlepeer-review


Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Metaanalysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for metaanalysis. Levels of 6thioguanine nucleotides (6TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 108 RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 108 RBC). We established a significant correlation between 6TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6TGN was 4.63 (95%CI 2.24; 9.57). An optimal cutoff of 135 pmol/8 × 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6methylmercaptopurine ribonucleotides (6MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 108 RBC; OR 4.28; 95%CI 3.20; 5.71). Levels of 6MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.

Original languageEnglish
Article number2216
Pages (from-to)1-34
Number of pages34
JournalJournal of Clinical Medicine
Issue number7
StatePublished - Jul 2020


  • Adverse events
  • Therapeutic drug monitoring
  • Thiopurines


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