Addition of Allopurinol for Altering Thiopurine Metabolism to Optimize Therapy in Patients with Inflammatory Bowel Disease

Abstract

Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.

Evolving Considerations for Thiopurine Therapy for Inflammatory Bowel Diseases—A Clinical Practice Update: Commentary

“…3 6TG has been used in patients with allergies to AZA or 6MP but has an increased risk of veno-occlusive disease and nodular regenerative hyperplasia, 4 and allopurinol has been used to reduce shunting of 6MP to 6MMP in nonresponders to AZA/6MP who develop transaminitis. 5 MTX is a folate antagonist targeting thymidylate biosynthesis and the enzyme thymidylate synthase. However, an exact mechanism of action in inflammatory disorders has not been elucidated.…”

Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience

“…1 Both azathioprine and 6-mercaptopurine are prodrugs that are metabolized to 6-thioguanine nucleotide (6-TGN), the main active metabolite (Figure 1). [2][3][4][5][6][7] In patients receiving azathioprine, the prodrug undergoes nonenzymatic splitting in the liver, which leads to formation of 6-mercaptopurine. The 6-mercaptopurine is further converted to 6-TGN through a series of metabolic transformations.…”

Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature

“…One such DI to consider occurs between the thiopurine immunosuppressant medications, azathioprine (AZA) and mercaptopurine (6‐MP), and XO inhibitors. Both AZA and 6‐MP are prodrugs that require conversion to their therapeutically active metabolites . Following oral administration, AZA is converted to 6‐MP and, as shown in Figure , 6‐MP can undergo further metabolism by three pathways resulting in production of a main therapeutically active metabolite, 6‐thioguanine (6‐TGN), and two inactive metabolites, 6‐methyl mercaptopurine and 6‐thiouric acid .…”

“…Both AZA and 6‐MP are prodrugs that require conversion to their therapeutically active metabolites . Following oral administration, AZA is converted to 6‐MP and, as shown in Figure , 6‐MP can undergo further metabolism by three pathways resulting in production of a main therapeutically active metabolite, 6‐thioguanine (6‐TGN), and two inactive metabolites, 6‐methyl mercaptopurine and 6‐thiouric acid . The cytotoxicity of AZA and 6‐MP is due, in part, to the incorporation of 6‐TGNs into deoxyribonucleic acid .…”

“…Simplified schematic of thiopurine metabolism and the impact of concomitant allopurinol . Solid arrows represent thiopurine metabolism via their three metabolic pathways.…”