title: Pharmacogenetics of drug-metabolizing enzymes: the prodrug hypothesis.
abstract: The hope of individualized drug therapy has been bolstered by the knowledge that drug-metabolizing enzymes can be affected by genetic polymorphisms. The initial flurry of potential examples has been muted somewhat by the failure of most predictions to be translated into clinical practice. Perhaps the only real example with reasonable evidence is that of azathioprine/6-mercaptopurine and thiopurine methyl-transferase. A few other examples such as tamoxifen, clopidogrel, irinotecan and warfarin warrant further discussion. An interesting feature of these drugs is that all except warfarin are prodrugs. We propose the hypothesis that prodrugs are over-represented in drugs that may be affected by genetic polymorphisms. Understanding this may assist our efforts to advance the field.
authors.affiliation: Department of Medicine, University of Otago - Christchurch, Christchurch 8140, New Zealand.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Begg
authors.forename: Nuala A
authors.initials: NA
authors.lastname: Helsby
authors.forename: Berit P
authors.initials: BP
authors.lastname: Jensen
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001379:Azathioprine / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004798:Enzymes / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D000077146:Irinotecan; D008780:Methyltransferases / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D004798:Enzymes; D011355:Prodrugs; D013629:Tamoxifen; D014859:Warfarin; D000077146:Irinotecan; D000077144:Clopidogrel; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D064417:Vitamin K Epoxide Reductases; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D014453:Glucuronosyltransferase; D001379:Azathioprine; D013988:Ticlopidine; D002166:Camptothecin