Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment

Asseldonk, Dirk P. van; Seinen, Margien L.; Boer, Nanne K. H. de; Bodegraven, Ad A. van; Mulder, Chris J.

doi:10.1016/j.crohns.2011.07.009

Cited by 35 publications

(36 citation statements)

References 26 publications

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“…30,31 Additionally, five patients with leukocytopenia on conventional thiopurine therapy benefitted from a switch to thioguanine therapy, hereby avoiding the formation of 6-MMP. 32 As shown in a large prospective cohort study by Chaparro and colleagues, 33 leukocytopenia is witnessed in about 4% of the patients treated with thiopurines after a median period of 7 months.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, allopurinol seems to have an enhancing effect on hypoxanthine‐guanine phosphoribosyltransferase (HGPRT), contributing to higher 6‐TGN formation as well . Additionally, five patients with leukocytopenia on conventional thiopurine therapy benefitted from a switch to thioguanine therapy, hereby avoiding the formation of 6‐MMP …”

Section: Discussionmentioning

confidence: 99%

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6‐methylmercaptopurine‐induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients

Meijer

Kreijne

Moorsel

et al. 2017

J of Gastro and Hepatol

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Background and Aim: Thiopurines have a favorable benefit-risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6-thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6-methylmercaptopurine (6-MMP). In this case series, we provide a detailed overview of 6-MMP-induced myelotoxicity in inflammatory bowel disease patients. Methods: We retrospectively scrutinized pharmacological laboratory databases of five participating centers over a 5-year period. Patients with leukocytopenia at time of elevated 6-MMP levels (>5700 pmol/8 × 10 8 red blood cells) were included for detailed chart review. Results: In this case series, we describe demographic, clinical, and pharmacological aspects of 24 cases of 6-MMP-induced myelotoxicity on weight-based thiopurine therapy with a median steady-state 6-MMP level of 14 500 pmol/8 × 10 8 red blood cells (range 6600-48 000). All patients developed leukocytopenia (white blood cell count 2.7 AE 0.9 × 10

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

6‐methylmercaptopurine‐induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients

Meijer

Kreijne

Moorsel

et al. 2017

J of Gastro and Hepatol

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“…Other reports have failed to demonstrate the same frequency or nature of hepatic injury during treatment with 6-thioguanine, and differences in dose and treatment duration have been proposed to explain the discrepant findings [186][187][188][189][190]. These experiences have justified the recommendation that 6-thioguanine be used in inflammatory bowel disease only after the failure of other options [191], and they have prompted the call for expert-based treatment guidelines [192].…”

Section: -Thioguaninementioning

confidence: 97%

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

Czaja¹

2012

IADT

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Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6- thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenter experiences.

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“…After switching the therapy to 6-thioguanine, immunosuppressive substances enter the metabolic pathway "further down", and a "shunting away" to 6-MMP nucleotides by TMPT is avoided. This strategy resulted in a reduced hepatotoxicity rate [25]. On the other hand, prior to any azathioprine treatment enzyme activity of TPMT should also be detected since patients with reduced enzyme activity exist, e.g.…”

Section: Discussionmentioning

confidence: 99%

Azathioprine Therapy in Multiple Sclerosis: Phosphoribosylated Metabolites and Thiopurine Methyltransferase Activity

Polychronopoulos¹,

Albrecht²,

Tafazzoli-Lari³

et al. 2014

TONEURJ

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Abstract:Objective: In this prospective study, we examined the association between azathioprine dose, levels of its phosphoribosylated metabolites, and the activity of thiopurine methyltransferase in patients with multiple sclerosis (MS). Materials/Methods: Clinical data and blood samples were collected from 27 MS patients who were undergoing azathioprine treatment. In red blood cells, thiopurine methyltransferase (TPMT) activity was determined, and after hydrolysis and cleavage of the phosphoribosyl residue, amounts of 6-thioguanine (6-TG), 6-methyl-thioguanine (6-MTG), 6-methylmercaptopurine (6-MMP) were measured. For clinical evaluation, the expanded disability status score (EDSS) and the multiple sclerosis functional composite (MSFC) were performed. Laboratory and clinical examinations were conducted twice with a 6-month-intervall. Results: Over a broad range of daily azathioprine dose, nearly constant levels of the immunosuppressive-active 6-TG (nucleotides) were found. There was, however, a marked relationship between daily azathioprine dose and 6-MMP nucleotide levels. Especially patients receiving an azathioprine dose of more than 1.5 mg/kg per day in particular presented an exponential increase in 6-MMP levels when TPMT activity was higher than 45 U/g Hb. All the biochemical measurements gave similar results when performed 6 months later. Conclusions: Patients with the combination of a high TPMT-activity and an azathioprine dose of more than 1.5 mg/kg/d exhibit significantly increased 6-MMP nucleotide levels. These patients are thus at risk for hepatotoxic side effects. Determination of TPMT activity before azathioprine therapy and monitoring of its metabolites might provide guidance for dose individualization.

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Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment

Cited by 35 publications

References 26 publications

6‐methylmercaptopurine‐induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients

6‐methylmercaptopurine‐induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

Azathioprine Therapy in Multiple Sclerosis: Phosphoribosylated Metabolites and Thiopurine Methyltransferase Activity

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