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)

Thiopurine drugs are used in the treatment of inflammatory bowel disease--as are sulphasalazine and its metabolite 5-aminosalicylic acid (ASA). S-Methylation catalyzed by thiopurine methyltransferase (TPMT) is a major pathway in the metabolism of thiopurines. The hypothesis was tested that TPMT might be inhibited by sulphasalazine or isomers of ASA. Sulphasalazine as well as 3-, 4- and 5-ASA inhibited recombinant human TPMT, with IC50 values of 78, 99, 2600 and 1240 microM, respectively. Kinetic studies demonstrated that the inhibition of TPMT by sulphasalazine and ASA isomers was non-competitive with regard to the thiopurine substrate, 6-MP, and was uncompetitive with regard to the methyl donor for the reaction, S-adenosyl-L-methionine. Our observations raise the possibility of a clinically significant drug-drug interaction in patients treated simultaneously with sulphasalazine and thiopurine drugs.
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PMID:Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. 764 Jan 56

6-mercaptopurine (6-MP) and azathioprine (AZA) are used to treat inflammatory bowel disease (IBD). Side effects include infection, leukopenia, hepatitis, and pancreatitis. The level of thiopurine methyltransferase (TPMT), which metabolizes 6-MP to 6-methylmercaptopurine, may reflect the risk of side effects. We sought to evaluate the relationship between the side effects of these medications and the TPMT level of pediatric patients with IBD. The medical records of our patients who were diagnosed with IBD and who received 6-MP or AZA were reviewed for measured TPMT levels. All red blood cell (RBC) TPMT levels were determined at the Mayo Medical Laboratories, Rochester, MN. The occurrence of leukopenia, elevated aminotransferases, and pancreatitis was evaluated. Twenty-two patients, mean age 13.7 years, received 6-MP or AZA and had TPMT levels measured. The TPMT levels ranged 10.7-27.5 U/mL RBC with a mean of 17.2 +/- 3.2 U/mL RBC. Two children had levels below the accepted norm of 13.8 U/mL RBC. One of these patients (50%) developed both elevation of aminotransferases and leukopenia. Of all, 20 children had normal levels, 3 (15.0%) exhibited side effects: hepatitis (n = 2) and leukopenia (n = 1). We conclude that side effects of 6-MP or AZA occur despite normal TPMT levels.
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PMID:Normal thiopurine methyltransferase levels do not eliminate 6-mercaptopurine or azathioprine toxicity in children with inflammatory bowel disease. 1087 70

Knowledge about the clinical pharmacology of medical therapy of inflammatory bowel disease has incrementally advanced. Small studies with mesalamine have suggested that intestinal mucosal concentrations of mesalamine may predict clinical response to mesalamine therapy. Increased expression of glucocorticoid receptor beta and increased expression of the multidrug resistance drug pump P-glycoprotein 170 have been proposed as markers of drug resistance to glucocorticoids. A baseline determination of thiopurine methyltransferase phenotype or genotype may predict early leukopenia in patients treated with azathioprine or 6- mercaptopurine. Serial measurement of erythrocyte 6-thioguanine nucleotides may be useful in tailoring the dose of these medications. A loading dose of intravenous azathioprine does not accelerate the time to response in patients with steroid-treated Crohn's disease; however, standard azathioprine may work more quickly than previously reported. Methotrexate, 15 to 25 mg/wk, is effective for the treatment of Crohn's disease (active or in remission), and there is no significant difference in the erythrocyte concentrations of methotrexate polyglutamate in patients with inflammatory bowel disease receiving 15 mg, compared with 25 mg, subcutaneously on a weekly basis.
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PMID:Clinical pharmacology of inflammatory bowel disease therapies. 1107 44

The calcineurin inhibitors cyclosporine and tacrolimus form the cornerstones of most immunosuppression protocols. Because of their variable pharmacokinetics, and their narrow therapeutic indices, post-transplant immunosuppressive drug monitoring is an essential part of patient care to minimize the risks of toxicity or acute rejection. Furthermore, a reduction in the rate of acute rejection has been shown to result in a lower rate of graft loss due to chronic rejection. The introduction of the microemulsion formulation of cyclosporine with its more consistent bioavailability has renewed interest in the use of alternative sampling strategies to the trough cyclosporine concentration. Both pharmacokinetic and pharmacodynamic considerations support the concept that determination of cyclosporine during the absorption phase (0-4 h) might offer a better prediction of cyclosporine immunosuppressive efficacy. Initial investigations suggest that monitoring a 2-h postdose concentration C(2) may provide a more efficacious alternative to trough monitoring for optimizing therapy with Neoral. Tacrolimus has a 10- to 100-fold greater in vitro immunosuppressive activity compared with cyclosporine. Consistent with its greater potency, therapeutic whole blood trough concentrations for tacrolimus are around 20-fold lower than the corresponding cyclosporine concentrations. The correlation between toxicity and tacrolimus trough concentrations appears to be stronger than that for acute rejection. The results from a concentration-ranging trial in primary kidney-transplantation and liver-transplantation trials all found a significant relationship between toxicity and tacrolimus trough levels. Azathioprine is converted in vivo to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. The latter are also responsible for the cytotoxic side effects. Reliance on blood counts to monitor azathioprine therapy can be misleading, and they do not provide information on immunosuppresive efficacy. More pertinent information can be obtained through the measurement of thiopurine S-methyltransferase activity and the quantification of intracellular 6-thioguanine nucleotides concentrations in red blood cells. Prospective studies have demonstrated the clinical utility of determining 6-thioguanine nucleotides to individualise immunosuppressive therapy with azathioprine not only in the field of transplantation, but also in inflammatory bowel disease.
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PMID:New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine. 1123 9

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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PMID:Pharmacokinetic considerations in the treatment of inflammatory bowel disease. 1170 60

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.
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PMID:Review article: monitoring for drug side-effects in inflammatory bowel disease. 1226 79

Thiopurine methyltransferase catalyzes the S-methylation of azathioprine (AZA), 6-mercapto-purine (6-MP) and thioguanine, medications widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease and solid organ transplant rejection. TPMT activity exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity, including fatal myelosuppression, after receiving standard doses of thiopurine medications. The molecular basis for low TPMT activity has been elucidated, leading to the development of assays for the three signature mutations, which account for the majority of mutant alleles. TPMT genotype is correlated with erythrocyte and leukemia blast cell TPMT activity and associated with a risk of toxicity after thiopurine therapy. Recent studies defined target starting doses for mercaptopurine based on TPMT genotypes. This polymorphism is one of the best models for the translation of genomic information to guide patient therapeutics.
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PMID:The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. 1196 6

This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.
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PMID:Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy: possible role of concomitant methotrexate. 1202 25

This article reviews the clinical pharmacology, adverse events, and comparative tolerability of the drugs commonly available for treating ulcerative colitis. Synthetic glucocorticoids are the most commonly used conventional corticosteroids in the treatment of ulcerative colitis. Corticosteroids can be expected to impact on every organ system and most metabolic activities of the body. Suppression of the hypothalamic-pituitary-adrenal axis is common, but reversible, with conventional corticosteroids, but not with newer topically-acting corticosteroids. A serious complication of corticosteroids in children is growth retardation. The frequent adverse effects associated with the use of corticosteroids have prompted the development of a new group of rectal agents with equivalent efficacy and a more benign adverse event profile such as prednisolone metasulfobenzoate, fluticasone propionate, tixocortol pivalate, beclomethasone dipropionate and budesonide. The incidence of adverse effects related to the use of sulfasalazine (5-aminosalicylic acid plus sulfapyridine) is high and is dose related. The most frequently reported adverse effect is intolerance, not allergy, and relates to the sulfapyridine moiety correlating with the acetylator phenotype. Tolerance to 5-aminosalicylic acid by 80 to 90% of those patients allergic to, or intolerant of, sulfasalazine has given further evidence suggesting that the sulfa moiety is responsible for much of the toxicity of sulfasalazine. However, 10 to 20% of patients who are sulfasalazine intolerant have similar reactions to 5-aminosalicylic acid formulations, indicating that the 5-aminosalicylic acid moiety is responsible for adverse events in some patients taking sulfasalazine. Adverse effects resulting from treatment with azathioprine and mercaptopurine can be divided into two categories: allergic-type reactions that appear to be dose-independent and nonallergic-type reactions that are probably dose- and metabolism-dependent. It is well established now that genotype and thiopurine methyltransferase activity have an important impact on the rate of adverse effects during azathioprine or mercaptopurine therapy. Adverse effects resulting from high dose cyclosporin therapy for inflammatory bowel disease include: renal insufficiency, hypertension, opportunistic infections, seizures, paresthesias, tremor, headache, gingival hyperplasia, hypertrichosis, and anaphylaxis with intravenous cyclosporin. In contrast, the incidence of adverse events was relatively low when low-dose oral cyclosporin was used. The incidence of adverse events associated with any of the medications used in the treatment of ulcerative colitis is difficult to assess and it is therefore hard to make a comparative evaluation. The broadening of the drug regimen available to the clinician has advanced our knowledge about the disease, and further development of more effective, less toxic agents can be anticipated in the future.
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PMID:Comparative tolerability of therapies for ulcerative colitis. 1211 42

6-mercaptopurine (6-MP) and its parent drug azathioprine (AZA) have been proven to be effective for both steroid-dependent and chronically active, or steroid-resistant inflammatory bowel disease, as well as for the prevention of relapse. Concerns about toxicity, delayed onset of action, and therapeutic failure (1 out of 3 patients) have restricted their use. Recent pharmacogenetic advances have led to the development of novel strategies to optimize and individualize therapy with AZA and 6-MP, maximizing efficacy while minimizing toxicity. We have defined a range of optimal therapeutic 6-MP metabolite levels, as well as an association of metabolite levels with medication-induced toxicity and the genotype of the main catabolic enzyme, thiopurine methyltransferase (TPMT). Measurement of 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/AZA, as well as for identifying individuals at increased risk for drug-induced toxicity.
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PMID:Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. 1268 87


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