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Letters to the Editor |
Sezione di Chimica Clinica, Dipartimento di Scienze, Morfologico-Biomediche, Università degli Studi di Verona, Verona, Italy
aAddress correspondence to this author at: Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università degli Studi di Verona, Ospedale Policlinico G.B. Rossi, Piazzale Scuro, 10, 37134 Verona, Italy. Fax 0039-045-8201889; e-mail ulippi{at}tin.it.
To the Editor:
Warfarin, a commonly prescribed anticoagulant drug used to prevent thrombosis, has a narrow therapeutic range, and small dose variations may result in hemorrhagic or thrombotic complications. The 2 key enzymes in the metabolism of warfarin are cytochrome P450 (CYP) 2C9 (CYP2C9 gene) and the C1 subunit of the vitamin K 2,3 epoxide reductase complex (VKORC1 gene). CYP2C9 accounts for up to 85% of the metabolism of the pharmacologically more potent S-warfarin enantiomer, and VKORC1, the 2nd key enzyme in warfarin metabolism, is responsible for recycling reduced vitamin K. In their recent article, Zhu et al. (1) concluded that genotyping both VKORC1 and CYP2C9, in conjunction with patient physical characteristics facilitated more precise estimation of warfarin dose and thus improved the efficiency of the dosage titration process. This conclusion was supported by the evidence that VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose. The findings of Zhu et al. (1) are consistent with earlier findings of Caldwell et al. (2), which demonstrated that CYP2C9 and VKORC1 each contribute substantially to dose variability and, together with clinical factors, explain 56% of the individual variability in stable warfarin dose. Taken together, these studies support the hypothesis that the formulation of dense genetic maps on the basis of single-nucleotide polymorphisms is an important approach to elucidating polygenic traits of drug response and, in combination with appropriate nongenetic factors, might help to define a warfarin dose–response phenotype.
We wish to point out additional aspects in the challenging endeavor to individualize warfarin therapy. First, the single contribution of the VKORC1 and CYP2C9 gene polymorphisms accounts for approximately 27% and 22% of the variability of maintenance dosage, respectively (1). Therefore, the aggregate variability of warfarin dosage explained by these 2 genes approaches 50% provided that other nongenetic factors are maintained fairly steadily throughout the titration period. Second, synthetic preservative substances, such as benzethonium chloride, are potent inhibitors of CYP2C9 activity in vitro, producing unpredictable effects of warfarin therapy (3). Third, the effectiveness of therapy is affected by numerous variables including drug interactions, illnesses, dietary or gastrointestinal features that alter the bioavailability of vitamin K, and physiologic variables that modify the synthetic or metabolic fate of the vitamin K-dependent coagulation factors. Thus, genetic algorithms might be efficient only when all these variables are stable (4). Finally, CYP2C9 genotyping may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached (5).
Although individualization of therapy based on genetic factors has great potential to improve efficiency and safety of the dosage titration process, genetic variability explains only a large fraction, not all, of the interindividual variation in warfarin dosage. Prospective studies that incorporate both gene testing and a variety of ethnic, clinical, pharmacological, and environmental variables, along with age, sex, and body weight, will be required to demonstrate the real safety, cost-effectiveness, and feasibility of individualized dosing regimens according to the statistical models for warfarin dose calculation.
Acknowledgments
Grant/funding support: None declared.
Financial disclosures: None declared.
References
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