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

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

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1
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands. y.deboer@vumc.nl

Abstract

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.

PMID:
23347359
DOI:
10.1111/apt.12223
[Indexed for MEDLINE]
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