title: Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis.
abstract: Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2-year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n = 53), compared to those who did not (n = 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P = 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 × 10(8) RBCs; P = 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (r(s) = -0.32; P = 0.007). An avTGN concentration of >220 pmol/8 × 10(8) RBCs best predicted remission, with an odds ratio of 7.7 (P = 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA-induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 × 10(8) RBCs).
  
  
  CONCLUSIONS
  TGN concentrations of >220 pmol/8 × 10(8) RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations.
authors.affiliation: Clinical Pharmacology Unit, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Dhaliwal
authors.forename: Rory
authors.initials: R
authors.lastname: Anderson
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Thornhill
authors.forename: Sarah
authors.initials: S
authors.lastname: Schneider
authors.forename: Elaine
authors.initials: E
authors.lastname: McFarlane
authors.forename: Dermot
authors.initials: D
authors.lastname: Gleeson
authors.forename: Lynne
authors.initials: L
authors.lastname: Lennard
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015331:Cohort Studies; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D019693:Hepatitis, Autoimmune / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D020714:Maximum Tolerated Dose; D008780:Methyltransferases / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; D000410:Alanine Transaminase; D001379:Azathioprine