Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6-Mercaptopurine and its prodrug azathioprine remain the mainstay of immunomodulator therapy for the maintenance of a steroid-free remission in patients with IBD. Recent evidence suggests that the cytotoxic and immunosuppressive effects of azathioprine might be mediated via the induction of lymphocyte apoptosis by its active metabolites, 6-thioguanine nucleotides. The therapeutic benefits of thiopurines have been shown to correlate with the concentration of 6-thioguanine nucleotides. Inherited differences in drug metabolism and disposition can significantly impact the safety and efficacy of these drugs. The thiopurine methyltransferase enzyme plays an important role in the metabolism of 6-mercaptopurine and azathioprine and in the determination of thiopurine cytotoxicity. By gaining an understanding of the pharmacology and metabolism of thiopurine therapy and putting it into the clinical context, clinicians will be able to optimize thiopurine therapy in IBD.
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PMID:Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. 1535 73

The determination of the thiopurine S-methyltransferase activity (TPMT; EC 2.1.1.67) has become an important issue during thiopurine therapy due to its known genetic polymorphism resulting in a wide range of TPMT activity. Therefore, the standard thiopurine drug regimen is associated with increased hematopoetic toxicity in patients with low or absent TPMT activity, whereas patients with high activity may be insufficiently treated. However, presently available methods are labour intensive and time consuming and tend towards too high or too low enzyme activity due to their methodological approach. The use of instable substrate solutions (6-MP or 6-TG), organic solvents like dimethyl sulfoxide and too high substrate and co-substrate saturation concentrations contribute to this phenomenon. We therefore, established an optimized and fast isocratic HPLC linked TPMT assay based on the enzymatic methylation of mercaptopurine or thioguanine in RBC lysates with S-adenosyl-l-methionine as methyl donor. Unspecific non-enzymatic methylation was not detectable. The recovery of 6-methyl-mercaptopurine was 97-102%, the intra- and interday variation between 1.0 and 5.0%, respectively. The assay dispenses with a time consuming extraction procedure with organic solvents, a heating step, and a gradient elution and is therefore, favourable for clinical routine application. The TPMT activity was measured in 62 untreated children with acute lymphoblastic leucemia at the time of diagnosis (activity = 34.0+/-10.6 nmol/g Hb/h, range: 11.5-55.4 nmol/g Hb/h) and in 12 adult healthy volunteers (62.8+/-7.7 nmol/g Hb/h, range: 48-82 nmol/g Hb/h) reflecting the wide measurable TPMT activity found in erythrocytes.
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PMID:Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes. 1589 17

In recent years, pharmacogenomics have received much attention from the increased expectations for so-called order-made medicine. It is experientially clear that inter-individual differences exist in the degree of efficacy and occurrence of adverse effects. These inter-individual differences are observed not only among anticancer chemotherapeutics but in almost all drugs. Several studies have revealed that genetic factors are involved in these inter-individual differences. To date, the relationships have been revealed between adverse effects of some anticancer drugs and polymorphisms of drug metabolizing genes. Such relationships include 5-FU and DPYD gene, methotorexate and MTHFR gene, irinotecan and UGT 1A1 gene and 6-MP and TPMT gene. By using information on these polymorphisms, it will be possible to predict the occurrence of adverse effects before using anticancer drugs. In particular, information on polymorphisms related to the possibly adverse effects of irinotecan is now given in its package leaflet. This means that order-made medicine is a step closer. In this review, we discuss the relationships between polymorphisms of genes and the adverse effects of anticancer drugs. Furthermore, we want to suggest the direction of further pharmacogenomic studies with an eye to the realization of order-made medicine.
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PMID:[SNPs associated with adverse effects]. 1628 25

6-Thioguanine (6-TG) seems to be an attractive alternative in both AZA- and 6-MP-intolerant and -resistant IBD populations. However, little is known of 6-TG pharmacokinetics, metabolite levels, and their correlation with drug efficacy and toxicity in IBD patients. This study reports the 6-TG pharmacokinetics in a population of IBD patients and the predictive value of metabolite concentrations. Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations were measured in 28 IBD patients at t = 1, 2, 4, and 8 weeks after starting 6-TG, 20 mg once daily. Outcome measures included mean 6-TGN concentrations (+/-95% confidence interval [CI95%]) and their associations with TPMT genotype, 6-TG dose, and hematological, hepatic, pancreatic, and efficacy parameters during the 8 week period. Steady-state 6-TGN concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days, and measured 856 (CI95% 715-997) pmol/8 x 10 RBCs. Large interpatient variability occurred at all time-points. No correlation was found between steady-state 6-TGN concentrations and drug dose per kilogram body weight. No significant differences in 6-TGN concentrations were found between patients with adverse events and patients without any event. Also, mean 6-TGN concentrations did not differ in patients with active disease versus patients in remission. In IBD patients on 6-TG treatment, large interindividual differences in metabolite concentrations occur. In our population, we could not demonstrate a clear relationship between 6-TGN concentrations on one hand and toxicity and efficacy on the other, as exist in AZA- and 6-MP-treated patients.
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PMID:Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. 1641 93

6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis...) but show a better survival rate while patients with high TPMT activity (wild type) present lower peripheral red blood cells 6-TGN concentrations and a higher risk of leukemia relapse. Genotyping remains crucial before 6-MP administration at diagnosis to identify patients with homozygous mutant TPMT genotype and therefore prevent severe and life-threatening toxicity, and to individualize therapy according to TMPT genotype. Follow-up of ALL treatment should preferentially be based on repeated determinations of intracellular active metabolites (6-thioguanine nucleotides) and methylated metabolites in addition to haematological surveillance.
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PMID:[Therapeutic drug monitoring of 6-thioguanine nucleotides in paediatric acute lymphoblastic leukaemia: interest and limits]. 2069 69

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.
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PMID:State-of-the-art: Immunosuppression and biologic therapy. 2092 83

Misconceptions are common in the care of patients with inflammatory bowel disease (IBD). In this paper, we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines, to review the related scientific evidence, and make appropriate recommendations. Prevention of errors needs knowledge to avoid making such errors through ignorance. However, the amount of knowledge is increasing so quickly that one new danger is an overabundance of information. IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems. With regard to the use of 5-aminosalicylates, the best practice may to be consider abandoning the use of these drugs in patients with small bowel Crohn' s disease. The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis; once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy. With regard to thiopurines, they seem to be as effective in ulcerative colitis as in Crohn' s disease. Underdosing of thiopurines is a form of undertreatment. Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse. Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine. Finally, thiopurine methyltransferase (TPMT) screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.
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PMID:Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease. 2194 13

Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.
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PMID:PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. 2489 64

6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.
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PMID:Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization. 2622 48

6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis. . . ) but show a better survival rate while patients with high TPMT activity (wild type) present lower peripheral red blood cells 6-TGN concentrations and a higher risk of leukemia relapse. Genotyping remains crucial before 6-MP administration at diagnosis to identify patients with homozygous mutant TPMT genotype and therefore prevent severe and life-threatening toxicity, and to individualize therapy according to TMPT genotype. Follow-up of ALL treatment should preferentially be based on repeated determinations of intracellular active metabolites (6-thioguanine nucleotides) and methylated metabolites in addition to haematological surveillance.
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PMID:[Not Available]. 2739 85


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