title: Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Christchurch Hospital, University of Otago, Christchurch, New Zealand.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Gardiner
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burt
authors.forename: Steven L
authors.initials: SL
authors.lastname: Ding
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology*; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000097:blood; D008875:Middle Aged; D013873:Thionucleotides / Q000097:blood*
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D001379:Azathioprine