Warfarin is an anticoagulant available as a racemic mixture. The R- and S-isomers differ with respect to relative plasma concentrations, clearance, potency, sites of metabolism, and cytochrome P450 (CYP) isoenzymes responsible for metabolism. S-Warfarin, the more potent isomer, is metabolized primarily by CYP2C9. Genetic polymorphisms resulting from single amino acid substitutions reduce the metabolic capability of 2C9. A reduction in warfarin metabolism due to genetic polymorphism may explain the increased warfarin response and bleeding episodes in some patients. Clinical studies showed an increased plasma level of S-warfarin, decreased clearance of S-warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles. Adverse outcomes associated with warfarin possibly could be avoided by identifying patients with variant alleles before therapy and starting therapy at low dosages.
Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed.
Although the average daily dose of the oral anticoagulant warfarin is 5 mg, there is wide interpatient variability in the dosage requirements (1). Dietary intake of vitamin K, concurrent medications, hepatic impairment, albumin levels, age, and adherence to therapy can profoundly influence dosage requirements. A growing body of evidence is pointing to genetic polymorphism of the major cytochrome P450 (CYP) isoenzyme responsible for warfarin metabolism as an additional explanation for this variability.Warfarin is given as a racemic mixture of Sand R-warfarin (1). S-warfarin is responsible for most of the therapeutic benefits and adverse ef-fects because it is approximately 5 times more potent than R-warfarin (1). However, its plasma concentration at steady state is only half that of R warfarin (2,3). Both S-and R-warfarin are metabolized by several different CYP isoenzymes to form inactive metabolites. S-warfarin is metabolized by CYP2C9 while R-warfarin is metabolized by CYP3A4, CYP1A1, and CYP1A2 (4,5). Of the CYP isoenzymes involved in warfarin metabolism, CYP2C9 is probably of the greatest importance because it is responsible for 80% to 85% of the metabolism of S-warfarin (5). Furthermore, the enzyme CYP2C9 is responsible for production of 7-hydroxywarfarin, which accounts for 45% of racemic warfarin metabolites (2).On a larger scale, CYP2C9 is important in that it is involved in approximately 20% of the CYPmediated reactions of available medications on the market. It is primarily responsible for the metabolism of phenytoin, losartan, irbesartan, tolbutamide, glipizide, torsemide, and some nonsteroidal anti-inflammatory drugs (6). It has Summary: The objective of this study was to report 2 cases of CYP2C9 genetic polymorphism and elevated warfarin S:R ratios in patients taking low doses of warfarin, and compare the observed characteristics with those in published reports. Two patients of different age groups and races were evaluated for CYP2C9 genotype and warfarin S:R ratios. The patients had been stabilized on weekly warfarin doses of 10.5 mg and 10 mg, respectively. Each patient was found to have at least 1 variant CYP2C9 allele. Elevated warfarin S:R ratios in both patients provided evidence for impaired metabolism of S-warfarin. This report of a CYP2C9*3 heterozygous individual taking a low dose of warfarin is consistent with previous reports in the literature. This summary of a CYP2C9*6 homozygous individual taking a low dose of warfarin is the first such published report. CYP2C9 genotyping in these patients provided a likely explanation for their continued low warfarin dosage requirements. Awareness of a patient's CYP2C9 genotype may provide an explanation for low warfarin dosage requirements in stable patients and may help in determining the optimal dose in patients being initiated on warfarin.
This study compared the frequency of variant cytochrome P450 2C9 (CYP2C9) alleles and warfarin S/R concentration ratio in patients who required low-dose (<2.5 mg/day) and average-dose (5+/-0.5 mg/day) warfarin. Patients who achieved a therapeutic international normalized ratio were recruited from the Atlanta Veterans Affairs Medical Center anticoagulation clinic. CYP2C9*2 and *3 alleles were determined by validated Taqman allelic discrimination assays. Warfarin S and R concentrations were determined by chiral capillary electrochromatography with electrospray ionization mass spectrometry. At least 1 variant allele was found in 66.7% and 22.2% of patients in the low-dose and average-dose groups, respectively (P= .001, chi(2)). The warfarin S/R concentration ratio was 0.665 (range, 0.162-3.58) and 0.452 (range, 0.159-2.36) for patients receiving low-dose and average-dose therapy, respectively (P= .097). A warfarin requirement of <2.5 mg/day and an elevated warfarin S/R concentration ratio were each associated with a higher frequency of variant CYP2C9 alleles.
The role of anticoagulation in the secondary prevention of noncardioembolic stroke has long been an area of debate. Previous evidence has shown that anticoagulation is unsafe at an International Normalized Ratio between 3.0 and 4.5. Results of the recently published Warfarin-Aspirin Recurrent Stroke Study (WARSS) suggest that there is no difference between warfarin and aspirin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Differences in the therapeutic interventions used may have had an effect on the differences in endpoints achieved as compared with previous studies. Results of ongoing trials are anticipated to further clarify the role of anticoagulation in the secondary prevention of stroke.
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