Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides

Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1238-42. doi: 10.1097/MEG.0b013e3282ffda37.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Azathioprine / administration & dosage
  • Azathioprine / adverse effects*
  • Azathioprine / blood
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / etiology*
  • Drug Administration Schedule
  • Drug Monitoring / methods
  • Female
  • Guanine Nucleotides / blood*
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / blood
  • Mercaptopurine / analogs & derivatives*
  • Mercaptopurine / blood
  • Middle Aged
  • Thionucleotides / blood*


  • Guanine Nucleotides
  • Immunosuppressive Agents
  • Thionucleotides
  • 6-thioguanylic acid
  • 6-methylthiopurine
  • Mercaptopurine
  • Azathioprine