Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis

Aliment Pharmacol Ther. 2013 Mar;37(6):640-6. doi: 10.1111/apt.12223. Epub 2013 Jan 24.


Background: Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease.

Aim: To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism.

Methods: We describe the clinical efficacy and tolerability of allopurinol-thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25-33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment.

Results: All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol-thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 10(8) red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 × 10(8) RBC (P = 0.01).

Conclusion: Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.

MeSH terms

  • Adult
  • Aged
  • Alanine Transaminase / metabolism
  • Allopurinol / therapeutic use*
  • Antimetabolites / therapeutic use*
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • Hepatitis, Autoimmune / blood
  • Hepatitis, Autoimmune / drug therapy*
  • Humans
  • Male
  • Mercaptopurine / analogs & derivatives*
  • Mercaptopurine / pharmacokinetics
  • Mercaptopurine / therapeutic use
  • Methyltransferases / metabolism
  • Middle Aged
  • Salvage Therapy
  • Thioguanine / pharmacokinetics


  • Antimetabolites
  • azathiopurine
  • Allopurinol
  • 6-methylthiopurine
  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase
  • Alanine Transaminase
  • Thioguanine