6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease

Dubinsky, Marla; Yang, Huiying; Hassard, Philip V.; Seidman, Ernest G.; Kam, Lori Y.; Abreu, María T.; Targan, Stephan R.; Vasiliauskas, Eric A.

doi:10.1053/gast.2002.32420

Cited by 454 publications

(455 citation statements)

References 29 publications

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“…Furthermore, there is evidence that patients who have very high levels of the S-methyl metabolite after treatment with 6-MP are also at risk for an adverse response to thiopurine therapy. However, in this case, the adverse response is hepatotoxicity (Dubinsky et al, 2002). Obviously, much remains to be learned about thiopurine metabolism and effect in patients.…”

Section: Tpmt Genetic Polymorphism: Discovery and Clinical Significancementioning

confidence: 91%

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

2006

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The thiopurine S-methyltransferase (TPMT) genetic polymorphism is one of the most 'mature' examples in pharmacogenetics. That is true because of its importance clinically for the individualization of thiopurine drug therapy and also because TPMT has provided novel insights into molecular mechanisms responsible for the functional effects of common genetic polymorphisms. This review will summarize the development of our understanding of the role of inheritance in the regulation of TPMT as well as the clinical implications of that genetic regulation. It will also summarize recent studies in which TPMT pharmacogenetics has enhanced our understanding of molecular mechanisms by which common polymorphisms influence or alter function. TPMT pharmacogenetics highlights the potential clinical importance of the translation of pharmacogenetics from bench to bedside, the potential for basic pharmacogenetic research to provide insight into mechanisms by which genetic polymorphisms can alter function, and the challenges associated with the achievement of both of those goals.

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Section: Tpmt Genetic Polymorphism: Discovery and Clinical Significancementioning

confidence: 91%

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

2006

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“…6-MP is subsequently metabolized to immunologically inactive 6-methylmercaptopurine metabolite ribonucleotides (6-MMP) by thiopurine methyltransferase (TPMT). Th e alternative competing pathway is conversion to 6-thioinosine 5-monophosphate (6-TImP) by intracellular hypoxanthineguanine phosphoribosyltransferase (HPRT) and then further enzymatic transformation by 2 separate metabolic pathways to produce either 6-thianoguanine metabolites (6-TGN) through an enzymatic cascade including inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthase (GMPS) or, alternatively, by TPMT to 6-MMP "subtherapeutic" 6-TGN levels, optimization of the levels was signifi cantly associated with improved response rates [83]. Importantly, there is a poor correlation between thiopurine dose and metabolite levels [72].…”

Section: Clinical Utility Of Tpmt Assessmentmentioning

confidence: 99%

“…In these patients, further escalation of a thiopurine dose frequently results in a disproportional escalation of 6-MMP levels [83], leading to discontinuation of these medications due to lack of effi cacy or hepatotoxicity [67]. Prompt identifi cation of this unique subgroup is crucially important for both safety and effi cacy considerations, as these patients may still benefi t from thiopurines if combined with medications that impact TPMT activity such as allopurinol or 5-aminosalicylates [85,86].…”

Section: Clinical Utility Of Tpmt Assessmentmentioning

confidence: 99%

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

2017

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Tumor necrosis factor (TNF)-α inhibitors and thiopurines are among the most important classes of medications utilized in the clinical management of Crohn's disease and ulcerative colitis. A signifi cant proportion of patients loses response to these agents or develops adverse eff ects during the course of the treatment. Monitoring of drug levels and anti-drug antibodies (for TNF-α inhibitors) and metabolite levels (for thiopurines) can provide valuable insight into the possible etiology of unfavorable outcomes and allow for an appropriate management strategy for these patients. Th is review summarizes the current knowledge on the clinical implications of therapeutic drug monitoring in infl ammatory bowel disease patients treated with TNF-α inhibitors and thiopurines.

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“…The drug is metabolized by multistep, multienzymatic pathways leading to wide interindividual variability. It is difficult to clinically optimize thiopurine therapy in IBD patients and 28% of patients have hepatotoxic and myelotoxic adverse reactions, and 9% of patients are resistant to therapy 7, 8, 9…”

Section: Introductionmentioning

confidence: 99%

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

et al. 2017

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Background and AimA lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients.MethodsIn this prospective study, 6‐thioguanine nucleotide (6‐TGN) and 6‐methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose‐related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature.ResultsOf the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non‐compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6‐TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6‐methylmercaptopurine levels ranged up to 4971 pmol/8 × 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose‐based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12–39%).ConclusionHalf of the patients in this study had low and a quarter had high 6‐TGN levels. One‐fourth of the patients needed dose modification. The dose‐based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients.

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6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease

Cited by 454 publications

References 29 publications

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

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