Hepatotoxicity allopurinol

A single case report describes allopurinol hepatotoxicity in a man given tamoxifen. 

Shah KA, Levin J, Rosen N, Greenwald E, Zumoff B. Allopurinol hepatotoxicity potentiated by tamoxifen. NY State J Med ( 9S2) 82, 1745-6. 

Paracetamol-induced hepatotoxicity can be prevented in animals with SOD, catalase and allopurinol (Kyle et al., 1987 Jaeschke, 1990 Tirmenstein and Nelson, 1990), and by N-acetyl-L-cysteine or methionine in humans (Meredith et al., 1986 Nelson, 1990). The protective efiect of allopurinol in mice only occurred at high concentrations, suggesting that its effect was related to scavenging of ROMs rather than inhibition of their production by XO (Jaeschke, 1990). 

Jaeschke, H. (1990). Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo-, the protective effect of allopurinol. J. Pharmacol Exp. Ther. 255, 935-941. 

Hepatotoxicity A few cases of reversible clinical hepatotoxicity have occurred in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase levels have been observed. If anorexia, weight loss or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. Perform periodic liver function tests during early stages of therapy. 

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

Major limitations of the use of allopurinol are allergy, hypersensitivity syndromes, hepatotoxicity, bone marrow suppression, nonspecific central nervous system and gastrointestinal side effects. Skin rash occurs in 2% and Steven-Johnson syndrome, although rare, may occur. The latter can cause life-threatening major organ system failure. 

Drug interactions allopurinol increases the toxicity of 6-MP by interfering with metabolism 75% dose reduction of 6-MP is required if used with allopurinol 6-MP reduces anticoagulant effects of warfarin concurrent use of 6-MP with other hepatotoxic drugs increases the risk of hepatotoxicity... 

Allopurinol (e.g., Zyloprim) Decreases uric acid levels by inhibiting xanthine oxidase, the enzyme which converts hypoxanthine to xanthine and xanthine to uric acid. Tophaceous gout, recurrent calcium oxalate stones. May exacerbate gout attacks. GI upset, hepatotoxicity, rash, Stevens-Johnson syndrome. ... 

An elderly man who had been taking allopurinol 300 mg daily for 12 years developed fever and marked increases in his serum levels of lactic dehydrogenase and alkaline phosphatase within a day of starting to take tamoxifen 10 mg twice daily. He rapidly recovered when the allopurinol was stopped. The reasons for the reaction are not understood, but the authors suggested that the increased hepatotoxic effect may have resulted from tamoxifen inhibiting allopurinol metabolism, thereby increasing the serum levels of allopurinol and its metabolite. The general importance of this isolated report is not known. 

In a retrospective study of inflammatory bowel disease patients treated with co-prescription of thiopurines and allopurinol, 20 of 25 patients with hepatotoxicity tolerated combination treatment and their liver function tests were normalised [75 ]. 

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