Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication

Authors

  • I. Cascorbi

    Corresponding author
    1. Institute of Pharmacology, Ernst Moritz Arndt University Greifswald, Germany
      Ingolf Cascorbi, MD, PhD, Institute of Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23D, D-17489 Greifswald, Germany. Tel. +49-3834-865650; fax: +49-3834-865651; e-mail: cascorbi@uni-greifswald.de
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Ingolf Cascorbi, MD, PhD, Institute of Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23D, D-17489 Greifswald, Germany. Tel. +49-3834-865650; fax: +49-3834-865651; e-mail: cascorbi@uni-greifswald.de

Abstract

Interindividual differences in the pharmacokinetics of a number of drugs are often due to hereditary polymorphisms of drug-metabolizing enzymes. Most important is cytochrome P4502D6 (CYP2D6), also known as debrisoquine/sparteine hydroxylase. It catalyzes hydroxylation or demethylation of more than 20% of drugs metabolized in the human liver, such as neuroleptics, antidepressants, some β-blockers and many others like codeine. About 7%−10% of Caucasians lack any CYP2D6 activity due to deletions and frame-shift or splice-site mutations of the gene. About 1%−3% of Middle-Europeans, but up to 29% of Ethiopians display gene duplications, leading to elevated so-called ultrarapid metabolization rates. Meanwhile there is now a much better understanding of the genetic background of poor, intermediate, extensive and ultrarapid metabolizers, enabling a more precise DNA genotyping-based prediction of plasma levels. Since there is evidence that deteriorated drug elimination partly accounts for drug side-effects, CYP2D6 genotyping could contribute to an individualized and therefore optimized drug therapy.

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