Genetic mechanisms for hypersensitivity and resistance to the anticoagulant Warfarin.
Warfarin is the therapeutic of choice for maintenance anticoagualtion therapy. A principle caveat of this medication is that the dosage required to achieve the desired therapeutic effect varies up to 120-fold between individuals. Currently, there are no reliable means of prospectively identifying which patients will require either unusually high or low dosages. This dilemma puts patients at risk of therapeutic failure or potentially life-threatening overdosage during a prolonged trial-and-error period of establishing an individualized medication strategy. Pharmacogenetic research has revealed that extreme differences in the drug dose required to achieve the desired therapeutic response can be attributed to genetic variation in the genes encoding drug metabolizing enzymes, and cellular receptor proteins. The anticoagulant Warfarin represents a model system where there is evidence to suggest that both pharmacokinetic and pharmacodynamic mechanisms contribute to the overall variability in patient response. Here the current understanding concerning the influence of genetic variation in Warfarin pharmacokinetics is reviewed and the potential for similar genetic mechanism impacting on the pharmacodynamic response in man is explored. Diagnostic testing to identify subjects requiring low-dose Warfarin therapy is discussed in light of potential confounding or coexisting resistance to the drug effects.
Linder
M W
MW
Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY 40292, USA. mwlind01@gwise.louisville.edu
D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000503:physiopathology; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D013923:Thromboembolism / Q000188:drug therapy; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D064417:Vitamin K Epoxide Reductases