Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Azathioprine (AZA) is an effective treatment for inflammatory bowel disease. The measurement of thiopurine methyltransferase (TPMT) activity levels helps to identify the one in 300 patients who are at risk of profound myelosuppression with standard doses of AZA. Thus, it is important that the measurement of TPMT activity is accurate. We report a case of misclassification of TPMT phenotype caused by prior blood transfusion. The patient appeared to have an intermediate level of TPMT enzyme activity as measured after the blood transfusion. However, following severe myelosuppression soon after starting AZA, her genotype was determined, which showed that she was homozygous for low TPMT activity. This report reviews some of the limitations in determining both the phenotype and the genotype of TPMT, especially following recent blood transfusion. The dilemma of whether or not to wait for the TPMT activity result before starting AZA is also discussed.
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PMID:Mistaken identity: misclassification of TPMT phenotype following blood transfusion. 1456 Jan 61

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) remain the mainstay of immunomodulator therapy for the maintenance of steroid-free remission in patients with inflammatory bowel disease (IBD). Traditional dosing strategies for initiation of thiopurines are often based on weight or empirically chosen. Dosing based on an understanding of an inherited difference in drug disposition and metabolism may provide a safer alternative. The thiopurine methyltransferase (TPMT) enzyme plays a pivotal role in the metabolism of 6-MP and AZA and is critical to the determination of thiopurine toxicity. The therapeutic benefits of thiopurines correlate best with concentration of the active 6-thioguanine (6-TGN) metabolites. Reports suggest that therapeutic response can be maximized when patients achieve therapeutic 6-TGN levels. Pharmacogenetic dosing based on TPMT and pharmacokinetic dosing based on 6-TGN levels may offer a safety and efficacy advantage over traditional dosing strategies and provide a novel mechanism for optimizing immunomodulator therapy in IBD.
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PMID:Optimizing immunomodulator therapy for inflammatory bowel disease. 1460 61

The polymorphic enzyme thiopurine methyltransferase (TPMT) is involved in the methylation of thiopurines. On comparing the phenotype with the genotype in Swedish patients with inflammatory bowel disease and healthy individuals, we found two discordant cases with low TPMT enzyme activity (0.3 and 0.4 U/ml packed red blood cells (pRBC). Genotyping by pyrosequencing revealed that they carried the nucleotide substitutions 460G>A and 719A>G, giving two possible genotypes (TPMT*1/*3A or TPMT*3B/*3C). DNA sequencing of exon III to X was performed in the patients and their parents. We identified an A>G transition in the start codon (exon III, 1A>G, Met>Val, TPMT*14) in one of the patients and her father (6.3 U/ml pRBC). The mother in this family carried the 460G>A and 719A>G nucleotide substitutions (TPMT*1/*3A; 5.0 U/ml pRBC). In the second family, sequencing revealed a G>A transition in the acceptor splice site in intron VII/exon VIII (IVS7 -1G>A, TPMT*15) in the patient and his mother (6.9 U/ml pRBC). His father was genotyped as TPMT*1/*3A (6.0 U/ml pRBC). Hence, we report the identification of two novel sequence variants, present in highly conserved nucleotide positions of the human TPMT gene, resulting in a loss of enzyme activity.
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PMID:Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity. 1508 71

The therapeutic efficacy and toxicity of many commonly employed drugs show interindividual variations that relate to several factors, including genetic variability in drug-metabolizing enzymes, transporters or targets. The study of the genetic determinants influencing interindividual variations in drug response is known as pharmacogenetics. The ability to identify, through preliminary genetic screening, the patients most likely to respond positively to a medication should facilitate the best choice of treatment for each patient; drugs likely to exhibit low efficacy or to give negative side-effects can be avoided. Among the medications used for inflammatory bowel disease, the best studied pharmacogenetically is azathioprine. The hematopoietic toxicity of azathioprine is due to single nucleotide polymorphisms in the thiopurine S-methyltransferase enzyme. Additionally, likely gene targets have been investigated to predict the response to glucocorticoids and infliximab, a monoclonal antibody against tumour necrosis factor that induces remission in approximately 30-40% of patients. However, no genetic predictor of response has been identified in either case.
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PMID:Pharmacogenetics of inflammatory bowel disease. 1515 30

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.
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PMID:Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. 1516 34

Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
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PMID:Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). 1516 6

Azathioprine is an immunosuppressive drug used in the treatment of inflammatory bowel disease. It is a prodrug that is hydrolysed to 6-mercaptopurine, which represents the active form. Azathioprine is also used in the treatment of leukaemia in children and in organ transplantation. Azathioprine treatment is associated with adverse effects such as leukopenia and aplasia. These adverse effects are related to a single nucleotide polymorphism, including the inability of cells to synthesize thiopurine methyltransferase (TPMT). TPMT is a detoxification enzyme that limits 6-thioguanine nucleotide production and thereby interferes with normal DNA and RNA synthesis. This review presents the different approaches used for azathioprine therapeutic monitoring in IBD treatment and discusses the discrepancies in recent clinical trials.
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PMID:[Genetic polymorphism and treatment of chronic bowel inflammatory diseases: the example of azathioprine]. 1519 72

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

Ulcerative colitis (UC) has been known as inflammatory bowel disease. Progress in UC management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. We here review about immunosuppressants in management of UC; Cyclosporine A (CsA) has been used for the induction therapy in steroid resistant refractory UC. Although it has been reported that CsA has high response rate in severe UC, long-term efficacy (maintenance of remission) has not been proven. To improve maintenance therapy, immunosuppressant has been re-considered in management of UC. In recent years, it has been reported that efficacy of 6-mercaptopurine/azathioprine in maintenance of remission of UC is superior to 5-aminosalicylate (5-ASA). Pharmacological studies have indicated thiopurine methyltransferase (TPMT) activity is essential for maintenance of blood concentration of 6-thioguanine nucleotide (6-TG).
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PMID:[Immunosuppressants for therapy of patients with ulcerative colitis]. 1588 Nov 78

Azathioprine, mercaptopurine, methotrexate, ciclosporin and tacrolimus all have their respective niches in the treatment of inflammatory bowel disease. These immunomodulators are potent and effective medications; however, they potentially have serious toxicity. To maximize benefit and minimize risk, clinicians must understand the mechanism of action, appropriate indications, range of toxicity and proper dosing of these medications. Furthermore, once initiating therapy, patients need to be monitored appropriately for evidence of efficacy and toxicity. This review includes the rationale behind recommendations for the management and monitoring of patients using immunomodulators. For the purine antagonists--azathioprine and mercaptopurine--the evidence for utility of thiopurine methyltransferase testing and mercaptopurine metabolite monitoring is addressed. The roles of liver biopsy and screening for methylenetetrahydrofolate reductase mutations in patients taking methotrexate are reviewed. With appropriate monitoring, the calcineurin inhibitors--ciclosporin and tacrolimus--can be used safely and effectively. Immunomodulators are important agents for the treatment of Crohn's disease and ulcerative colitis, and prescribing clinicians should be comfortable recognizing both their value and their limitations.
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PMID:Review article: practical management of inflammatory bowel disease patients taking immunomodulators. 1596 74


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