Pharmacokinetics and immune reconstitution following discontinuation of thiopurine analogues: Implications for drug withdrawal strategies

Shomron Ben-Horin, Gert Van Assche, Yehuda Chowers, Ella Fudim, Bella Ungar, Orit Picard, Miri Yavzori, Uri Kopylov, Ren Mao, Min Hu Chen, Yael Peled, Itai Gueta, Rami Eliakim, Ronen Loebstein, Noa Markovits*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background and Aims: Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation. Methods: The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+T-cell proliferation, following an initial exposure toTSST1 and 6-mercaptopurine [6MP], separately or combined. Results: All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9]. Conclusions: Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.

Original languageEnglish
Pages (from-to)1410-1417
Number of pages8
JournalJournal of Crohn's and Colitis
Issue number12
StatePublished - 28 Nov 2018


  • Immune reconstitution
  • Inflammatory bowel disease
  • Thiopurine analogues


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