ABCMdb

ABCC2 p.Gly460Ala

Predicted by SNAP2:	A: D (75%), C: D (75%), D: D (91%), E: D (91%), F: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (80%), P: D (91%), Q: D (80%), R: D (91%), S: D (80%), T: D (85%), V: D (85%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Advances of molecular clinical pharmacology in gas... Am J Ther. 2010 Sep-Oct;17(5):e137-62. Prandota J
Advances of molecular clinical pharmacology in gastroenterology and hepatology.
Am J Ther. 2010 Sep-Oct;17(5):e137-62., [PMID:19433977]

Abstract [show]
During developmental age, differences in pharmacodynamic reactions to several drugs may reflect polymorphisms of genes encoding drug-transporting proteins, receptors, drug targets, and gene products, whose disturbed activity sometimes plays an important role in certain diseases. Administration of drugs with a narrow therapeutic index may quite easily be associated with changes in pharmacokinetics and development of adverse drug reactions, which occasionally may cause fatalities. In such cases, polypragmasy and resulting drug interactions may enhance effects of changes in drug-metabolizing enzymes' activities. Phenotyping and genotyping of patients slowly are finding their place in some therapeutic regimens used in clinical gastroenterology and hepatology. At present, some assays to measure, for example, thiopurine S-methyltransferase activity are already commercially available. Polymorphisms of CYP450 enzymes, interleukins, and altered gene expression play an important role in some patients' various gastrointestinal tract and liver diseases. Herbal drugs also affect proinflammatory and antiinflammatory cytokine and nitric oxide balance in the body. Therapeutic use of recombined proteins, such as infliximab, natalizumab, onercept, humanized antibody to integrin alpha-4 beta-7, or IFN-beta in some large-bowel diseases increased therapeutic efficacy. IFN-alpha used in the patients with chronic hepatitis C improved cellular immunity in these subjects and exerted antiviral activity. Practical application of progress in pharmacogenetics, pharmacokinetics, pharmacodynamics, and use of bioproducts in novel therapeutic regimens has opened therapeutic frontiers and increased clinical safety.

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79 The patient`s age and renal function status may elicit changes in erythrocyte TPMT activity, and blood transfusion performed during the 2 months preceding treatment may lead to false results.8 In addition, drug interactions may also exert deleterious effects, for example, concomitant administration of AZA and mesalamine (often used in ulcerative colitis) leads to an increase in 6-TGN blood levels and enhances risk of myelotoxicity, which can be explained by reversible inhibition of mesalamine metabolism by TPMT.65,78 In the patients receiving both thiopurines and mesalamine, adverse effects were observed more frequently.78,79 TPMT activity may be inhibited also by therapeutic plasma levels of furosemide, thiazide diuretics, sulfasalazine, 5-acetylsalicylic acid, and nonsteroid antiinflammatory Table 7. Characteristics of thiopurine S-methyltransferase main alleles. Allele Functional nucleotide change Amino acid change Enzyme activity Associated phenotype Allele prevalence (%) TPMT*1 None None Normal EM 96.1 TPMT*2 G238C Ala80Pro Decreased PM 2-5 TPMT*3A G460A A719G Ala154Thr Tyr240Cys None PM 3.5-6.5 TMPT*3B G460A Ala154Thr None PM 0.35 TPMT*3C A719G Tyr240Cys None PM 0.7 PM, poor metabolizer; EM, efficient metabolizer drugs.67,80 Conversely, thiopurine therapy alone may increase activity of TPMT.8,65,73 In some cases, monitoring of therapeutic 6-TGN blood concentrations may be as important as TPMT genotyping or phenotyping. Login to comment