title: Pharmacogenetic prediction of individual variability in drug response based on CYP2D6, CYP2C9 and CYP2C19 genetic polymorphisms.
abstract: Interindividual variability in drug response depends on a number of genetic and environmental factors. The metabolic enzymes are well known for their contribution to this variability due to drug-drug interactions and genetic polymorphisms. The phase I drug metabolism is highly dependent upon the cytochrome P450 mono-oxygenases (CYP) and their genetic polymorphism leads to the variable internal drug exposures. The highly polymorphic CYP2C9, CYP2C19 and CYP2D6 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and contribute significantly to adverse drug reactions and therapeutic failures. In this review, two attractive and easily implementable approaches are highlighted to recommend drug doses ensuring similar internal exposures in the face of these polymorphisms. The first approach relies on subpopulation-based dose recommendations that consider the original population dose as an average of the doses recommended in genetically polymorphic subpopulations. By using bioequivalence principles and assuming linear gene-dose effect, dose recommendations can be made for different metabolic phenotypes. The second approach relates area under the curve to two characteristic parameters; the contribution ratio (CR), computes for the contribution of the metabolic enzyme and the fractional activity (FA), considers the impact of the genetic polymorphism. This approach provides valid and error free internal drug exposure predictions and can take into consideration genetic polymorphisms and drug interactions and/ or both simultaneously. Despite certain advantages and limitations, both approaches provide a good initial frame-work for devising models to predict internal exposure and individualize drug therapy, one of the promises from human genome project.
authors.forename: Shafqat Rasul
authors.initials: SR
authors.lastname: Chaudhry
authors.forename: Sajjad
authors.initials: S
authors.lastname: Muhammad
authors.forename: Moritz
authors.initials: M
authors.lastname: Eidens
authors.forename: Marco
authors.initials: M
authors.lastname: Klemm
authors.forename: Dilaware
authors.initials: D
authors.lastname: Khan
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Department of Neurosurgery, University of Bonn, Sigmund-Freudstrasse 25, D-53105 Bonn, Germany. shafqatrasul@yahoo.com.
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Weisshaar
mesh_terms: D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
chemical_list: D004364:Pharmaceutical Preparations; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6