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

Seinen, Margien L.; Boer, Nanne K. H. de; Smid, Kees; Asseldonk, Dirk P. van; Bouma, Gerd; Bodegraven, Adriaan A. van; Peters, Godefridus J.

doi:10.1080/15257770.2011.597371

Cited by 22 publications

(18 citation statements)

References 16 publications

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“…30 The enhanced HGPRT activity corroborates and extends preliminary data. 25 Ding and colleagues recently reported a correlation between the activity of HGPRT and 6-TGN concentrations, which was not observed in this study possibly due the small sample size. 31 Nonetheless, the enhanced HGPRT activity may at least in part explain the rise in 6-TGN concentrations as HGPRT is the first enzyme, responsible for the generation of 6-TGN.…”

Section: 29contrasting

confidence: 40%

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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Section: 29contrasting

confidence: 40%

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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“…Allopurinol inhibits XO but has no direct inhibiting effect on TPMT (8 ). An open-label prospective study of allopurinol combined with lowdose thiopurine therapy showed increased HPRT activity (9 ). This increase in HPRT activity, which catalyzes the first step in 6-TGN production, is consistent with the 6-TGN increase, but it does not fully explain the simultaneous dramatic decrease in 6-MMPR, which leads to an improved metabolite ratio.…”

Section: Discussionmentioning

confidence: 55%

Poor Response to Thiopurine in Inflammatory Bowel Disease: How to Overcome Therapeutic Resistance?

et al. 2013

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A 24-year-old woman (53 kg) with a 5-year history of steroid-dependent ulcerative colitis with mild and extensive ulcerations presented to the gastroenterology clinic for symptom recurrence. She was given 100 mg/ day (1.9 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) azathioprine (AZA) 5 for 1 month, after which the dose was increased to 125 mg/ day (2.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). Four months later, the patient was tapered off steroid therapy. Her symptoms persisted after 7 months of AZA therapy, however, and she experienced gastrointestinal side effects. The patient was switched to another thiopurine drug, 6-mercaptopurine (6-MP), at 75 mg/day (1.4 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), which was well tolerated but similarly ineffective (8 stools daily). A brief course of steroid therapy rapidly produced a substantial but shortlived clinical improvement.To understand this patient's unresponsiveness to 2 thiopurine agents, we quantified thiopurine metabolites (1 ) 1 year after initiating AZA therapy. Intraerythrocyte concentrations of 6-thioguanine nucleotides (6-TGNs) were low (132 pmol/8 ⅐ 10 8 erythrocytes; therapeutic interval, 230 -400 pmol/8 ⅐ 10 8 erythrocytes), and 6-methylmercaptopurine ribonucleotides (6-MMPRs) were very high (11 666 pmol/8 ⅐ 10 8 erythrocytes; therapeutic interval, Ͻ5800 pmol/8 ⅐ 10 8 erythrocytes). A second quantification of thiopurine metabolites 3 months later confirmed these results (6-TGNs, 127 pmol/8 ⅐ 10 8 erythrocytes; 6-MMPR, 26 304 pmol/8 ⅐ 10 8 erythrocytes). The patient had an unusual and extremely high thiopurine S-methyltransferase (TPMT) activity in erythrocytes [61.5 nmol ⅐ h Ϫ1 ⅐ (mL erythrocytes) Ϫ1

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“…However, in the study by van Egmond et al, 19 TPMT activity was not correlated with those who had the highest 6-methyl mercaptopurine levels. Moreover, Seinen et al 24 reported that combination therapy enhanced the activity of HGPRT in patients with IBD. Therefore, it is also possible that the combination of indirect effects of allopurinol on 6-MP metabolism fortuitously results in the shunting of metabolism to avoid hepatotoxicity.…”

Section: Discussionmentioning

confidence: 98%

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

Giamanco

Cunningham

Klein

et al. 2016

Journal of Pediatric Hematology/Oncology

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6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

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

Cited by 22 publications

References 16 publications

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

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

Poor Response to Thiopurine in Inflammatory Bowel Disease: How to Overcome Therapeutic Resistance?

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

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