Genetic mechanisms for hypersensitivity and resistance to the anticoagulant Warfarin

Warfarin is the therapeutic of choice for maintenance anticoagualtion thera py. A principle caveat of this medication is that the dosage required to ac hieve the desired therapeutic effect varies up to 120-fold between individu als. Currently, there are no reliable means of prospectively identifying wh ich patients will require either unusually high or low dosages. This dilemm a puts patients at risk of therapeutic failure or potentially life-threaten ing 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 t herapeutic response can be attributed to genetic variation in the genes enc oding drug metabolizing enzymes, and cellular receptor proteins. The antico agulant Warfarin represents a model system where there is evidence to sugge st that both pharmacokinetic and pharmacodynamic mechanisms contribute to t he 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 th e pharmacodynamic response in man is explored. Diagnostic testing to identi fy subjects requiring low-dose Warfarin therapy is discussed in light of po tential confounding or coexisting resistance to the drug effects. (C) 2001 Elsevier Science B.V. All rights reserved.