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

• Published in: European journal of gastroenterology & hepatology Vol. 20; no. 12; pp. 1238 - 1242
• Main Authors: Gardiner, Sharon J, Gearry, Richard B, Burt, Michael J, Ding, Steven L, Barclay, Murray L
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins, Inc 01-12-2008; Lippincott Williams & Wilkins
• Subjects: Adult; Azathioprine - administration & dosage; Azathioprine - adverse effects; Azathioprine - blood; Biological and medical sciences; Chemical and Drug Induced Liver Injury - blood; Chemical and Drug Induced Liver Injury - etiology; Drug Administration Schedule; Drug Monitoring - methods; Drug toxicity and drugs side effects treatment; Female; Gastroenterology. Liver. Pancreas. Abdomen; Guanine Nucleotides - blood; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - blood; Medical sciences; Mercaptopurine - analogs & derivatives; Mercaptopurine - blood; Middle Aged; Pharmacology. Drug treatments; Thionucleotides - blood; Toxicity: digestive system; Antineoplastic agent; Purine derivatives; Toxicity; Thiopurine derivatives; Hepatic disease; Concentration; Tioguanine; Treatment; Antimetabolic; 6-mercaptopurine; Gastroenterology; Nucleotide; Digestive diseases; Immunosuppressive agent; Azathioprine; Dose; Hepatotoxicity; therapeutic drug monitoring; Mercaptopurine
• ISSN: 0954-691X; 1473-5687
• 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/8×10 RBC) resulted in severe hepatotoxicity (liver failure in two cases) associated with unrecognized extremely high 6-MMPN concentrations of 26 000–40 000 pmol/8×10 RBC. These cases illustrate a risk with thiopurine dose adjustment based on monitoring of 6-TGN metabolites without also monitoring 6-MMPN.