Observations on the use of allopurinol in combination with azathioprine or mercaptopurine

Duley, John A.; Chocair, Pedro Renato; Florin, Timothy H.

doi:10.1111/j.1365-2036.2005.02703.x

Cited by 32 publications

(24 citation statements)

References 12 publications

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“…Because HGPRT is also the first step in formation of methylated 6-MP nucleotides, an increase in 6-MMP was anticipated; however, 6-MMP concentrations appeared to be decreased. Duley [15] hypothesized that an oxipurinol metabolite can inhibit the methylation reaction, leading to a decrease of 6-MMP. This combination of low-dose allopurinol and thiopurines was well tolerated.…”

Section: Discussionmentioning

confidence: 99%

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

Seinen¹,

Boer²,

Smid³

et al. 2011

Nucleosides, Nucleotides and Nucleic Acids

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Thiopurines are crucial in the treatment of inflammatory bowel disease. The phenotype of pivotal metabolic enzymes determines whether thioguanine nucleotides (6-TGN) are generated in clinically sufficiently high levels. The first step in activation of thiopurine prodrugs to 6-TGN is catalysis by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Often, patients exhibit a clinically unfavorable metabolism, leading to discontinuation of conventional thiopurine therapy. The combination of allopurinol and low-dose thiopurine therapy may optimize this variant metabolism, presumably by affecting enzyme activities. We performed a prospective pharmacodynamic study to determine the effect of combination therapy on the activity of HGPRT. The activity of HGPRT and 6-TGN concentrations was measured in red blood cells during thiopurine monotherapy and after 4 weeks of combination therapy. The activity of HGPRT was also measured after 12 weeks of combination therapy. From the results, we conclude that combination therapy increases the activity of HGPRT and subsequently 6-TGN concentrations.

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Section: Discussionmentioning

confidence: 99%

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

Seinen¹,

Boer²,

Smid³

et al. 2011

Nucleosides, Nucleotides and Nucleic Acids

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“…Some evidence suggests that allopurinol gets converted to oxypurinol by aldehyde oxidase which then gets converted to oxypurinol riboside monophosphate which is a competitive inhibitor of TPMT. 24 Recently Blaker et al suggested that allopurinol mediated increase in thioxanthine levels also inhibit the TPMT enzyme activity. 25 An unidentified cofactor is also thought to play a role in shunting of thiopurine metabolism from 6MMP pathway to 6TG pathway by allopurinol.…”

Section: Role Of Allopurinol In Optimizing Thiopurine Therapy In Patimentioning

confidence: 99%

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Deswal

Srivastava

2017

Journal of Clinical and Experimental Hepatology

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Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH. ( J CLIN EXP HEPATOL 2017;7:55-62)

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“…Oxypurinol is further converted to oxypurinol riboside monophosphate, which as a TPMT substrate may be responsible for (competitive) TPMT inhibition and the subsequent decrease in 6-MMPR production. 33 In addition, there is evidence that 2-hydroxy-6-mercaptopurine (2OHMP) is a TPMT inhibitor. 34 Also, 2OHMP can be formed from 6MP by AOX, especially when XO is inhibited (Fig.…”

Section: 29mentioning

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

Boer

et al. 2013

Journal of Crohn's and Colitis

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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.

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Observations on the use of allopurinol in combination with azathioprine or mercaptopurine

Cited by 32 publications

References 12 publications

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

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

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