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Genetic Polymorphisms and Cardiovascular Drug Metabolism

  • A. R. Boobis
  • T. Shiga
  • R. J. Edwards
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 160)

Abstract

Both the therapeutic and the adverse effects of drugs can be profoundly influenced by the activity of enzymes of drug metabolism. Biotransformation is effected by a number of families of structurally and functionally related enzymes, which inactivate and ultimately enable the excretion of therapeutic agents. The enzymes of drug metabolism exhibit broad and overlapping substrate specificities. Many of these enzymes are now known to exhibit polymorphic expression, due often to point mutations in the structural gene. The result may be a large difference in metabolic activity, and consequently in the pharmacokinetics, between phenotypes. Examples of polymorphic enzymes include CYP2D6, CYP2C9, CYP2C19 and NAT2. Some drug transporters such as ABCB1 (P-glycoprotein) are also polymorphic. The consequences of such polymorphism will depend upon a number of factors, including the steepness of the concentration-effect curve, the contribution of the polymorphic pathway to overall elimination and the magnitude of other sources of variability in the effect of the polymorphic enzyme. In this last case, whilst it might be possible to demonstrate clear differences in effect between phenotypes in healthy volunteers, other sources of variability, including the disease itself, may dominate differences in response in patients. There are some clear examples of the importance of polymorphic drug metabolism in the effects of drugs, such as CYP2C9 and warfarin and NAT2 and hydralazine. However, it is likely that the extent to which genotyping might benefit the individual patient will be established only in adequate clinical studies.

Keywords

Pharmacokinetics Metabolism Enzymes CYP450 Drug transporters 

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© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • A. R. Boobis
    • 1
  • T. Shiga
    • 1
  • R. J. Edwards
    • 1
  1. 1.Section on Clinical Pharmacology, Division of MedicineImperial College LondonLondonUK

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