Low‐dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease

Gerven

et al. 2013

Aliment Pharmacol Ther

SUMMARY BackgroundTen 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.

Section: Resultsmentioning

confidence: 99%

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

Gerven

et al. 2013

Aliment Pharmacol Ther

“…Recently, combination therapy of allopurinol and low-dose thiopurine in IBD patients was also shown to prevent non-hepatic adverse events that had occurred during standard dosed thiopurine monotherapy. 17 Moreover, long-term treatment with this combination is effective and well-tolerated in IBD patients. 16,18 The pharmacokinetic explanation of the substantial increase in 6-TGN and decrease in 6-MMPR concentrations upon combination therapy is not completely clarified, but may be explained by alterations in the activities of XO, TPMT and HGPRT.…”

Section: Introductionmentioning

confidence: 99%

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Seinen

Asseldonk

Journal of Crohn's and Colitis

et al. 2013

Introduction: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. Methods: A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. Conclusion: Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

“…Finally, allopurinol, a xanthine oxidase inhibitor, has been utilized to improve metabolite levels and to reduce hepatotoxicity induced by AZA/6-MP [74][75][76][77][78] . Theoretically, the inhibition of xanthine oxidase should lead to increases in both 6-TG and 6-MMP; however, data actually suggest a unexpected decrease in 6-MMP levels [79] .…”

Section: Drug-induced Liver Injury Due To Agents Used Tomentioning

confidence: 99%

Hepatotoxicity of Agents Used in the Management of Inflammatory Bowel Disease

Khokhar

Lewis²

2010

Dig Dis

Patients with inflammatory bowel disease (IBD) are at risk for hepatobiliary disease and toxicity, and the diagnosis of drug-induced liver disease in patients being treated for IBD can represent a clinical challenge. There are a number of disease states associated with IBD, which are primary sclerosing cholangitis, cholangiocarcinoma and autoimmune hepatitis. There is a wide spectrum of hepatic injury that can occur from the agents used to treat IBD, such as acute or chronic hepatic injury directly attributable to the drugs used to treat IBD (e.g. sulfasalazine, mesalamine, thiopurines, methotrexate, TNF antagonists, quinolone antibiotics); liver toxicity from drugs used to treat complications of immunomodulators and TNF antagonists (e.g. isoniazid for treatment of reactivation tuberculosis), and exacerbation of underlying chronic viral hepatitis with infliximab and other TNF antagonists. Thiopurines are also associated with the development of hepatic vascular lesions, such as nodular regenerative hyperplasia and peliosis hepatic. In addition, biologics can be associated with the reactivation of underlying chronic viral hepatitis, mandating universal screening prior to initiation of TNF-alpha antagonist therapy.