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


OBJECTIVE
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).


CONCLUSIONS
Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands. y.deboer@vumc.nl
Y S
YS
de Boer
N M F
NM
van Gerven
N K H
NK
de Boer
C J J
CJ
Mulder
G
G
Bouma
C M J
CM
van Nieuwkerk
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000493:Allopurinol / Q000627:therapeutic use*; D000963:Antimetabolites / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D019693:Hepatitis, Autoimmune / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D016879:Salvage Therapy; D013866:Thioguanine / Q000493:pharmacokinetics
D000963:Antimetabolites; C488629:azathiopurine; D000493:Allopurinol; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D000410:Alanine Transaminase; D013866:Thioguanine