Where is warfarin metabolised

Certain common changes polymorphisms in the VKORC1 gene account for 20 percent of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism. The polymorphisms associated with warfarin resistance often differ by population and ethnic background. Warfarin prevents inhibits the action of the VKORC1 enzyme by binding to the enzyme and preventing it from binding to and activating the clotting proteins, stopping clot formation.

This reduction in warfarin binding causes incomplete warfarin resistance and results in a higher dose of warfarin needed to inhibit the VKORC1 enzyme and stop the clotting process.

While changes in specific genes affect how the body reacts to warfarin, many other factors, including sex, age, weight, diet, and other medications, also play a role in the body's interaction with this drug. The polymorphisms associated with this condition are inherited in an autosomal dominant pattern , which means one copy of the altered gene in each cell is sufficient to result in warfarin resistance.

However, different polymorphisms affect the activity of warfarin to varying degrees. Additionally, people who have more than one polymorphism in a gene or polymorphisms in multiple genes associated with warfarin resistance have a higher tolerance for the drug's effect or are able to process the drug more quickly.

Genetics Home Reference has merged with MedlinePlus. The bleeding tendency in the coadministration of these drugs is suggested in clinical practice, but is not completely elucidated in this study This derivative of amphetamine inhibits CYP2C19 and, consequently, an interaction with warfarin is theoretically possible, since there are no studies analyzing its concomitant use The study carried out by Loomis et al.

Nevertheless, it is possible that this inhibition only occurs with higher doses of amitriptyline or nortriptyline than those used in clinical practice No change in the half-life of warfarin was noted with therapeutic doses of these TCAs There are no clinical reports and no scientific studies on the possible interactions between warfarin and the TCAs - bupropion, clomipramine, doxepin and imipramine, the tetracyclic antidepressants maprotiline and mirtazapine, and the noradrenaline reuptake inhibitors amoxapine and desipramine.

Of the antidepressants analyzed with prior studies or reports, the only one that showed relevant effects in clinical practice were, in decreasing order, paroxetine, venlafaxine, fluoxetine, and duloxetine. Both physicians and pharmacists should investigate all medications and supplements for patients receiving treatment with warfarin.

Additionally, clinicians who deal with patients under chronic therapy with this medication should restrict the use of drugs and supplements that show interactions not yet established with it for absolutely essential indications, and when appropriate, maintain cautious follow-up. Considering the high rate of combined prescription of drugs with a high potential for interacting with warfarin, extreme care is needed to avoid adverse reactions.

When the patient requires the concomitant use of medicines and several drugs are available to treat the condition, those that do not interact with warfarin should be favored. It is appropriate that the anticoagulant effect be monitored more frequently in patients who use multiple drugs or who have changed any of the drugs of treatment. One retrospective study estimated that one third of the adverse effects related to the use of anticoagulant drugs were avoidable with early diagnosis and changes in treatment.

Keeping well organized notes on the prescribed drugs is also important. In addition, the list of drugs should be revised regularly and updated with the patient, with special attention given to the great assortment of "natural" drugs and products or herbal preparations that the patient uses temporarily.

Patients should be given guidance on the importance of taking drugs and supplements. Abrir menu Brasil. Abrir menu. Warfarin; Antidepressive agents; Drug interactions; Anticoagulants. Jacobs LG. Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly. Cardiol Clin. Frequency of concurrent use of warfarin with potentially interacting drugs.

Reducing warfarin medication interactions: an interrupted time series evaluation. Arch Intern Med. Hardy JL, Sirois A. Reduction of prothrombin and partial thromboplastin times with trazodone. Rio de Janeiro: Churchill Linvingstone; Goodman LS, Gilman A. Rio de Janeiro: Mc Graw Hill; Batlouni M. Anticoalugantes orais. O'Reilly RA.

In: Katzung BG, editor. Rio de Janeiro: Guanabara Koogan; Simply stated, when a patient has little or no enzyme activity, there is little or no enzyme activity to inhibit. Thus, having a genetic polymorphism that results in reduced VKORC1 function will increase a patient's sensitivity to warfarin. Likewise, these patients may be at increased risk from drug interactions that increase warfarin plasma concentrations because their VKORC1 does not function normally to produce vitamin K-dependent clotting factors.

It is possible that some patients, based on their VKORC1 genotype, will be more susceptible to changes in vitamin K intake or drugs that alter vitamin K absorption or production eg, antibiotics.

A better understanding of variations in VKORC1 activity will be helpful in predicting the magnitude of effect seen with agents affecting vitamin K.

The changes in warfarin response during concomitant administration of interacting drugs also will be affected by these genetic differences. More studies will be required to assess which patients are more or less likely to exhibit exaggerated responses to drugs that interact with warfarin metabolism. Genotyping was performed by three different methods based on polymerase chain reaction PCR. The biotinylated fragment is captured on a streptavidin-coated microtiter plate and rendered single stranded.

The two alleles are detected in two separate reactions using a single-nucleotide primer extension with radioactively labelled deoxynucleotide triphosphate dNTP for the variable base.

CYP3A5 was genotyped with pyrosequencing, which is a method based on the quantification of pyrophosphate release during synthesis. Single base extension of multiple primers is performed by a cycle sequencing reaction with fluorescently labelled dideoxynucleotide triphosphates. The aim was to analyse which of the studied explanatory variables have a significant effect on mean warfarin dose and mean warfarin dose per BW. To describe how the measured factors affect dose, means were adjusted for an imbalance in other variables by LS means.

Adjustment for multiple comparisons was performed by the Tukey—Kramer method. The significance level was set at 0. ABCB1 haplotypes were estimated according to Phase, which is a statistical method for haplotype reconstruction from population data. Goodman and Gilman's. Google Scholar. Linder MW. Gentic mechanisms for hypersensitivity and resistance to the anticoagulant warfarin. Clin Chim Acta ; : 9— Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation.

Thromb Haemost ; 86 : — Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician ; 3 : — Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med ; 95 : — Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.

Chest ; : S—S. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J ; 3 : — Vitamin K intake and sensitivity to warfarin in patients consuming regular diets.

Thromb Haemost ; 81 : — Interactions of warfarin with drugs and food. Ann Intern Med ; : — The risk for and severity of bleeding complications in elderly patients treated with warfarin. Interindividual variability in sensitivity to warfarin—nature or nurture? Clin Pharmacol Ther ; 70 : — Harder S, Thurmann P. Clinically important drug interactions with anticoagulants.

An update. Clin Pharmacokinet ; 30 : — Kaminsky LS, Zhang Z. Human P metabolism of warfarin. Pharmacol Ther ; 73 : 67— Pharmacogenetics of oral anticoagulants.

Pharmacogenetics ; 13 : — Association of polymorphisms in the cytochrome P CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet ; : — Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

J Am Med Assoc ; : — Pharmacogenetics ; 6 : — Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics ; 5 : —