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Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications(一)

作者:神马 整理:本网站论文网 录入时间:2011-12-13 23:15:33

  作者:Stephen Bernarda, Kathleen A. Nevilleb, Anne T. Nguyenb, David A. Flockhartb

  【关键词】 CYP2D6,polymorphism,•,Hepatic,metabolism,•,5-HT3-receptor,antagonist,antiemetics,•,Genetic,variability

  LEARNING OBJECTIVES

  After completing this course, the reader will be able to:

  List the four different genotypes for CYP2D6 polymorphism.

  Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme.

  List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme.

  ABSTRACT

  

  DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. Theexact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity.

  Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT3-receptor antagonists, whichare used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism.

  Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country’s wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drugdrug interactions increases.

  INTRODUCTION

  

  It is well recognized that the majority of drugs are metabolized via microsomal enzymes localized in the liver and, to a lesser extent, the small intestine [1]. The activity of many drugs depends on their interaction with enzymes of the cytochrome P450 (CYP) system. These enzymes, which are responsible for drug activation and metabolism, display wide interindividual variation that can lead to significant interindividual differences in drug clearance. Such metabolic differences can alter the doseresponse relationship and can have a number of possible outcomes, ranging from therapeutic failure to a higher incidence of adverse events and toxicity [1, 2]. Genetic polymorphisms in drug-metabolizing enzymes are a ma

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