Warfarin dosing and cytochrome P450 2C9 polymorphisms

2004 ◽  
Vol 91 (06) ◽  
pp. 1123-1128 ◽  
Author(s):  
F. Johnson ◽  
Janina Longtine ◽  
Nils Kucher ◽  
Hylton Joffe ◽  
Ruliang Xu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Low Dose ◽  
Pcr Amplification ◽  
Warfarin Dose ◽  
High Dose ◽  
Restriction Enzyme Digestion ◽  
Cytochrome P450 2C9 ◽  
In The Wild ◽  
Warfarin Dosing ◽  
Compound Heterozygotes

SummaryTwo cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize warfarin inefficiently. We assessed the extent to which these polymorphisms explain very low warfarin dose requirements and hemorrhagic complications after excluding non-genetic determinants of warfarin dosing. In this retrospective observational study, 73 patients with stable warfarin doses for ≥1 month and International Normalized Ratios (INR) of 2.0–3.0 were enrolled from our Anticoagulation Clinic. Seventeen patients required ≤2 mg (low-dose), 41 required 4–6 mg (moderate-dose), and 15 required ≥10 mg (high-dose) of daily warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9 polymorphisms independently predicted low warfarin requirements after adjusting for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83–160.78). At least one polymorphism was present in every patient requiring ≤1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high-dose groups, respectively. All homozygotes and compound-heterozygotes for the variant alleles were in the low-dose group. Rates of excessive (INR>6.0) anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100 patient-years in the wild-types, heterozygotes, and compound heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound heterozygotes and homozygotes have low warfarin requirements even after excluding liver disease, excessive alcohol or acetaminophen consumption, low body weight, advancing age, and drug interactions. These polymorphisms increase the rate of excessive anticoagulation, but this risk does not appear to be associated with higher bleeding rates when anticoagulation status is closely monitored.

Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery

2020 ◽  
Vol 77 (13) ◽  
pp. 1018-1025
Author(s):  
Maura Harkin ◽  
Brittany Powers Shaddix ◽  
Stephen B Neely ◽  
Leigh A Peek ◽  
Katy Stephens ◽  
...  
Keyword(s):  
Low Dose ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Primary Objective ◽  
Cardiothoracic Surgery ◽  
Entire Study Period ◽  
Entire Study ◽  
Frequent Monitoring ◽  
Safety Outcomes ◽  
Warfarin Dosing

Abstract Purpose Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS. Methods A descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate. Results Twenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission. Conclusion The majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

scholarly journals Evaluating the effect of Ganoderma lucidum polysaccharides on five cytochrome P450 isozymes with cocktail probe drugs in rats by LC–MS/MS

2019 ◽  
Vol 4 (1) ◽  
Keyword(s):  
Cytochrome P450 ◽  
Ganoderma Lucidum ◽  
Low Dose ◽  
Antioxidant Activities ◽  
Plasma Concentrations ◽  
Control Group ◽  
High Dose ◽  
Positive Effects ◽  
Ganoderma Lucidum Polysaccharides ◽  
Tandem Mass Spectrometric

Ganoderma lucidum polysaccharides (GLPs) are commonly used as health-promoting medicine and dietary supplement due to the positive effects in immune modulation, antitumor and antioxidant activities. However, whether GLPs executes other uncharacterized effects is largely unclear. The rats were pre-primed with GLPs and then administrated with canonical “cocktail probes” of cytochrome P450 (CYP450) isozymes including caffeine, tolbutamide, dextromethorphan, omeprazole, and midazolam. The plasma concentrations of probes at each indicated time point were simultaneously detected using the designed high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. The results suggested that GLPs could increase the accumulated levels of caffeine, tolbutamide and midazolam in plasma as compared to control group. Besides, GLPs reduced the concentration of dextromethorphan in blood at high dose, while elevated it at low dose. GLPs could inhibit the activities of CYP1A2, and CYP3A4, additionally; GLPs at low dose suppressed the activity of CYP2D6, which demonstrated that drugs co-administrated with GLPs might require strictly evaluating the dose relation.

scholarly journals GENETIC POLYMORPHISMS OF CYTOCHROME P450 2C9, VITAMIN K EPOXIDE-REDUCTASE SUBUNIT 1 AND WARFARIN DOSING IN PATIENTS WITH PERMANENT ATRIAL FIBRILLATION

2016 ◽  
Vol 1 (4) ◽  
pp. 18-22
Author(s):  
A O Rubanenko ◽  
Yu V Shchukin
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Polymorphisms ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Cytochrome P450 2C9 ◽  
Risk Of Bleeding ◽  
Permanent Atrial Fibrillation ◽  
Epoxide Reductase ◽  
Warfarin Dosing ◽  
Permanent Form

Aim - to assess the influence of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dosing in patients with permanent form of atrial fibrillation. Methods. The study included examination of 100 patients with coronary heart disease and permanent form of atrial fibrillation; mean age 60.5±5.8 years. Conclusion. In patients with permanent form of atrial fibrillation, genotypes CYP2C9*1/*3, TT and GG genotypes of VKORC1 are associated with low warfarin dose, compared to other genotypes. Genotype CYP2C9*1/*3 increases the risk of bleeding complication during warfarin therapy.

Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin

2004 ◽  
Vol 91 (01) ◽  
pp. 87-94 ◽  
Author(s):  
Charles Eby ◽  
Paul Milligan ◽  
Gerald Banet ◽  
Jill Duncan ◽  
Howard McLeod ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Maintenance Dose ◽  
Smoking Status ◽  
A Priori ◽  
Warfarin Dose ◽  
Demographic Variables ◽  
Nucleotide Polymorphisms ◽  
Cytochrome P450 2C9 ◽  
Single Nucleotide ◽  
Dietary History

SummaryKnowledge of pharmacogenetics may help clinicians predict their patients’ therapeutic dose of warfarin, thereby decreasing the risk of bleeding during warfarin initiation. Our goal was to use pharmacogenetics to develop an algorithm that uses genetic, clinical, and demographic factors to estimate the warfarin dose a priori. We collected a blood sample, demographic variables, laboratory values, smoking status, names of medications, and dietary history from 369 patients who were taking a maintenance dose of warfarin. Using polymerase chain reaction, we genotyped each participant for the presence of 8 polymorphisms in the cytochrome P450 2C9 system. Using multiple regression, we quantified the association between warfarin dose and all factors. Advanced age, lower body surface area (BSA), and the presence of cytochrome P450 2C9 *2 or *3 single nucleotide polymorphisms were strongly associated (P < 0.001) with lower warfarin dose: the maintenance dose decreased by 8% per decade of age, by 13% per standard deviation decrease in BSA, by 19% per 2C9*2 allele, and by 30% per 2C9*3 allele. Warfarin doses were 29% lower in patients who took amiodarone, 12% lower in patients who took simvastatin, 21% lower in patients whose target INR was 2.5 rather than 3.0, and 11% lower in white rather than African-American participants (P < 0.05 for these comparisons). An algorithm that included these factors and one of borderline significance (sex), explained 39% of the variance in the maintenance warfarin dose. Use of this pharmacogenetic model had potential to prevent patients from being overdosed when initiating warfarin: we estimate that only 24 (6.5%) patients would have been overdosed by >2 mg/day with pharmacogenetic dosing compared to 59 (16%) patients who would have been overdosed if they had been prescribed the empirical dose of 5 mg/day (P < 0.001). In conclusion, the maintenance warfarin dose can be estimated from demographic, clinical, and pharmacogenetic factors that can be obtained at the time of warfarin initiation.

Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients

2007 ◽  
Vol 120 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Rina Kimura ◽  
Kotaro Miyashita ◽  
Yoshihiro Kokubo ◽  
Yasuhisa Akaiwa ◽  
Ryoichi Otsubo ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Vitamin K ◽  
Warfarin Dose ◽  
Japanese Patients ◽  
Cytochrome P450 2C9 ◽  
Vitamin K Epoxide Reductase ◽  
Epoxide Reductase
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