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)

There is an increased risk of developing bone marrow depression and infections during azathioprine therapy for inflammatory bowel disease. Patients with low or absent thiopurine S-methyltransferase (TPMT) activity have an increased risk of developing myelotoxicity. We describe a patient who developed pancytopenia combined with cytomegalovirus pneumonia after several years of azathioprine use. The bone marrow depression was probably caused by the viral infection, as all others causative factors were unlikely. Surprisingly, we observed grossly elevated TPMT activity (182 nmol/g/h) during the recovery phase, following the pancytopenic period. After complete recovery of the bone marrow suppression, TPMT activity returned to usual reference activity (43 nmol/g/h). This remarkable change in enzymatic activity of TPMT may be explained by differences in the age of red blood cells, as younger erythrocytes have a higher TPMT activity. Determination of a patient's TPMT status by phenotyping should therefore not be performed just after bone marrow depression or in cases of activated erythropoieses.
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PMID:Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age. 1852 Jun 12

Azathioprine and 6-mercaptopurine have been used for many years in the treatment of inflammatory bowel disease. Approximately 0.3% of the population are homozygous for variant alleles associated with extremely low thiopurine S-methyltransferase enzyme activity. We describe the case of a young patient with ulcerative colitis, homozygous for TPMT*3A alleles, who suffered fatal azathioprine-induced myelotoxicity after standard dosing with azathioprine. Screening for decreased activity of TPMT in patients prior to azathioprine treatment is advised to minimize the risk of drug-induced toxicity.
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PMID:Fatal myelotoxicity after azathioprine treatment. 1860 May 23

Genetic variation in thiopurine S-methyltransferase (TPMT) is a major factors for wide variation in the metabolism and safety of thiopurine drugs. We investigated the frequency of functional gene polymorphisms in 396 patients with inflammatory bowel disease and 300 healthy subjects. Frequencies of functionally deficient alleles TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3B in the patient group were 0.1%, 4.3%, 0.1%, and 0.4%, respectively, and were similar to those of healthy subjects in the Czech population. Our results provide necessary information for pharmacoeconomic studies in the Czech Republic.
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PMID:Polymorphisms of the TPMT gene in the Czech healthy population and patients with inflammatory bowel disease. 1860 May 49

Recently, conventional therapies for inflammatory bowel disease (IBD) have not received the same amount of attention as biologic therapies, yet they remain the backbone of therapy for IBD because of their efficacy, safety, and relatively low cost. Advances in efficacy and safety continue because of modifications in drug dosing and monitoring. Higher doses of mesalamine per pill, together with once-daily dosing, may help to optimize drug delivery and patient compliance. Budesonide, an effective agent for both induction and short-term remission maintenance in Crohn's disease, is devoid of many of the toxicities common to corticosteroids. Assessments of thiopurine methyltransferase and metabolite levels are helping to fine-tune dose optimization for the thiopurines azathioprine and 6-mercaptopurine. The oral calcineurin inhibitors tacrolimus and cyclosporine have been shown to have expanded roles in IBD, and methotrexate may be useful in some patients with refractory ulcerative colitis. Probiotics are showing promise for maintenance of remission in Crohn's disease, ulcerative colitis, and pouchitis.
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PMID:Optimizing conventional therapy for inflammatory bowel disease. 1900 15

Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testing becomes available locally as a clinical service.
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PMID:Thiopurine methyltransferase and thiopurine metabolite testing in patients with inflammatory bowel disease who are taking thiopurine drugs. 1960 82

Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent.
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PMID:Drug monitoring in inflammatory bowel disease: helpful or dispensable? 1978 71

There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P=0.903) or ITPA (P=0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy.
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PMID:Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs. 1996 28

Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice azathioprine (AZA) or 6-mercaptopurine (6-MP) are not effective in one-third of patients and up to one-fifth of patients discontinue thiopurine therapy due to adverse reactions. The observed interindividual differences in therapeutic response and toxicity to thiopurines are explained to a large extent by the variable formation of active metabolites, which is at least partly caused by genetic polymorphisms of the genes encoding crucial enzymes in thiopurine metabolism. In this in-depth review we discuss the genetic polymorphisms of genes encoding for glutathione S-tranferases, xanthine oxidase, thiopurine S-methyltransferase, inosine triphosphate pyrophosphatase, hypoxanthine phosphoribosyltransferase, inosine monophosphate dehydrogenase and multidrug resistance proteins. Pharmacogenetic knowledge in this field has increased dramatically and is still rapidly increasing, but the translation into practical guidelines with tailored advices will cost much effort in the near future.
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PMID:Pharmacogenetics of thiopurines in inflammatory bowel disease. 2020 60

In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.
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PMID:Pharmacogenomics in the treatment of inflammatory bowel disease. 2023 96

Azathioprine is commonly used in the treatment of autoimmune hepatitis (AIH). Few data are available on drug monitoring of azathioprine metabolites in patients with AIH, especially in pediatric patients. The purpose of this study was to investigate intracellular thiopurine metabolites in children with AIH and to assess the relevance of drug monitoring compared with the efficacy and toxicity. Data from 28 patients with AIH treated by azathioprine for at least 3 months were recorded. 6-Thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine nucleotides (6-MeMPN) concentrations and TPMT activity were determined by high-performance liquid chromatography. Blood cell counts and liver function tests were also collected and the clinical outcome was documented. A wide interindividual variability in 6-TGN and 6-MeMPN concentrations was observed with values ranging from 51 to 1966 pmol/8 x 10(8) red blood cells (RBCs) for 6-TGN and from 42 to 8189 pmol/8 x 10(8) RBCs for 6-MeMPN. A total of 61.4% of the patients achieved remission and only 32.6% of these children had 6-TGN values within the target range proposed for inflammatory bowel disease (250-450 pmol/8 x 10(8) red blood cells). No difference in metabolite concentrations was observed between children in remission and those with active disease. Azathioprine dosage was significantly related to 6-TGN and 6-MeMPN levels (r = 0.308, P < 0.001 and r = 0.405, P < 0.001, respectively). A significant negative correlation was observed between 6-TGN concentrations and erythrocyte and lymphocyte counts, whereas 6-MeMPN was not related to blood cell counts. Although leukocyte counts were not related to 6-TGN concentrations, patients with leucopenia exhibited higher 6-TGN values than those without leucopenia (median values 438 pmol/8 x 10(8) RBCs versus 405 pmol/8 x 10(8) RBCs, respectively). Thiopurine metabolite monitoring appears useful in identifying the myelotoxicity and the hepatotoxicity as a result of azathioprine with disease recurrence and to assess adherence to therapy. A further larger study will be required to confirm the optimal recommended target for thiopurine metabolites to achieve remission in patients with AIH.
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PMID:Monitoring of azathioprine metabolites in pediatric patients with autoimmune hepatitis. 2047 3


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