Drug/Small Molecule:
phenprocoumon

Available Guidelines

  1. Dutch Pharmacogenetics Working Group Guideline for phenprocoumon and CYP2C9
  2. Dutch Pharmacogenetics Working Group Guideline for phenprocoumon and VKORC1

last updated 08/10/2011

Dutch Pharmacogenetics Working Group Guideline for phenprocoumon and CYP2C9

Summary

For patients treated with phenprocoumon, consider checking INR more frequently in individuals with CYP2C9 2*/2*, 2*/3*, or 3*/3* genotype.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenprocoumon based on CYP2C9 genotypes [Article:21412232]. They recommend checking INR more frequently in individuals with CYP2C9 2*/2*, 2*/3*, or 3*/3* genotype.

Genotype Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
CYP2C9 *1/*2 None Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): death; arrhythmia; unanticipated myelosuppression
CYP2C9 *2/*2 Check INR more frequently Published controlled studies of good quality\* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): death; arrhythmia; unanticipated myelosuppression
CYP2C9 *1/*3 None Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): death; arrhythmia; unanticipated myelosuppression
CYP2C9 *2/*3 Check INR more frequently Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): death; arrhythmia; unanticipated myelosuppression
CYP2C9 *3/*3 Check INR more frequently Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10{^}9^/l; leucopenia 1.0-2.0x10{^}9^/l; thrombocytopenia 25-50x10{^}9^/l; severe diarrhea

last updated 08/10/2011

Dutch Pharmacogenetics Working Group Guideline for phenprocoumon and VKORC1

Summary

For patients treated with phenprocoumon, consider checking INR more frequently in patients with the AA genotype at VKORC1 rs9934438.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenprocoumon based on VKORC1 genotype [Article:21412232]. They found that VKORC1 rs9934438 genotype contributes to dose variability. However, they make no dosing recommendations at this time "because of strict international normalized ratio monitoring by the Dutch Thrombosis Service."

Genotype Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
VKORC1 rs9934438 AG None Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5
VKORC1 rs9934438 AA Check INR more frequently. Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5

PharmGKB has no annotated drug labels with pharmacogenomic information for this drug/small molecule. If you know of a drug label with PGx, send us a message.

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2C9 *2 N/A N/A N/A
No VIP available No VIP available VA CYP2C9 *3 N/A N/A N/A
No VIP available No VIP available VA CYP3A4 *1B N/A N/A N/A
No VIP available No Clinical Annotations available VA
rs1043550 *4A>G, *77A>G, 128409225A>G, 66442068A>G
A > G
3' UTR
No VIP available No Clinical Annotations available VA
rs1051740 19537412T>C, 226019633T>C, 26837T>C, 337T>C, EPHX1: Y113H, NM_000120.2: c.337T>C, NT_004559.13: g.2221786T>C, Tyr113His, c.337T>C, mRNA 378T>C, mRNA 612T>C, p.Tyr113His
T > C
Missense
Tyr113His
No VIP available No Clinical Annotations available VA
rs1057910 1075A>C, 47545517A>C, 47639A>C, 96741053A>C, CYP2C9*3, CYP2C9*3:Ile359Leu, CYP2C9: I359L, CYP2C9:359Ile>Leu, CYP2C9:Ile359Leu, Ile359Leu, mRNA 11A>C
A > C
Missense
Ile359Leu
No VIP available No Clinical Annotations available VA
rs10871454 30988079C>T, 31048079C>T, 379-1168C>T, STX4
C > T
Intronic
No VIP available No Clinical Annotations available VA
rs12714145 214+597G>A, 44-1143G>A, 6317G>A, 64609228C>T, 85787341C>T, GGCZ, intron 2 C/T
C > T
Intronic
No VIP available No Clinical Annotations available VA
rs1799808 -228C>T, 128175862C>T, 17924525C>T, 4867C>T
C > T
5' Flanking
No VIP available No Clinical Annotations available VA
rs1799809 -215G>A, 128175875G>A, 17924538G>A, 4880G>A
G > A
5' Flanking
No VIP available No Clinical Annotations available VA
rs1799853 430C>T, 47506511C>T, 8633C>T, 96702047C>T, Arg144Cys, CYP2C9*2, CYP2C9:144Arg>Cys, CYP2C9:Arg144Cys, mRNA 455C>T
C > T
Missense
Arg144Cys
No VIP available CA VA
rs2108622 1297G>A, 14389G>A, 15990431C>T, 23454G>A, 7253233C>T, CYP4F2 exon 11, CYP4F2: C>T, CYP4F2: V433M, CYP4F2:V433M, V433M, Val433Met, c.1297G>A, mRNA 1347G>A, p.Val433Met
C > T
Missense
Val433Met
No VIP available No Clinical Annotations available VA
rs35599367 20493C>T, 37399159G>A, 522-191C>T, 99366316G>A, CYP3A4*22
G > A
Intronic
No VIP available No Clinical Annotations available VA
rs4086116 13788C>T, 47511666C>T, 482-334C>T, 96707202C>T
C > T
Intronic
No VIP available No Clinical Annotations available VA
rs510317 -348A>G, -348A>T, -402A>G, -402A>T, 113759754A>G, 113759754A>T, 1255760A>G, 1255760A>T, 4650A>G, 4650A>T
A > T
A > G
5' Flanking
No VIP available No Clinical Annotations available VA
rs510335 -347G>A, -347G>C, -347G>T, -401G>A, -401G>C, -401G>T, 113759755G>A, 113759755G>C, 113759755G>T, 1255761G>A, 1255761G>C, 1255761G>T, 4651G>A, 4651G>C, 4651G>T
G > A
G > T
G > C
5' Flanking
No VIP available No Clinical Annotations available VA
rs7294 *134G>A, *237G>A, 31042321C>T, 31102321C>T, 8956G>A, VKORC1:3730G>A, VKORC1:G9041A
C > T
3' UTR
No VIP available CA VA
rs9923231 -1639G>A, -1639G>C, -1639G>T, 12609882C>A, 12609882C>G, 12609882C>T, 31096368C>A, 31096368C>G, 31096368C>T, 3588G>A, 3588G>C, 3588G>T, VKORC1: -1639G>A, VKORC1:-1639, VKORC1:G3673A, upstream -1639G>A
C > G
C > T
C > A
Not Available
No VIP available CA VA
rs9934438 173+1000C>T, 174-136C>T, 31044878G>A, 31104878G>A, 6399C>T, VKORC1: 1173C>T, VKORC1:C1173T, VKORC1:C6484T
G > A
Intronic
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Fenprocumone [DCIT]
  • Phenprocoumarol
  • Phenprocoumarole
  • Phenprocoumone
  • Phenprocumone
Trade Names
  • Falithiom
  • Falithrom
  • Fencumar
  • Liquamar
  • Marcoumar
  • Marcumar
  • Marcuphen
Brand Mixture Names

PharmGKB Accession Id:
PA450921

Description

Coumarin derivative that acts as a long acting oral anticoagulant.

Source: Drug Bank

Indication

Used for the prevention and treatment of thromboembolic disease including venous thrombosis, thromboembolism, and pulmonary embolism as well as for the prevention of ischemic stroke in patients with atrial fibrillation (AF).

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Phenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

Source: Drug Bank

Pharmacology

Phenprocoumon, a coumarin anticoagulant, thins the blood by antagonizing vitamin K which is required for the production of clotting factors in the liver. Anticoagulants such as phenprocoumon have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage (damage caused by an inadequate blood supply to an organ or part of the body). However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Phenprocoumon is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites. Cytochrome P450 2C9 is the principal form of human liver P-450 responsible for metabolism.

Source: Drug Bank

Protein Binding

99%

Source: Drug Bank

Absorption

Bioavailability is close to 100%

Source: Drug Bank

Half-Life

5-6 days

Source: Drug Bank

Toxicity

50=500 mg/kg. Symptoms of overdose includes suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries).

Source: Drug Bank

Chemical Properties

Chemical Formula

C18H16O3

Source: Drug Bank

Isomeric SMILES

CCC(c1ccccc1)c2c(c3ccccc3oc2=O)O

Source: OpenEye

Canonical SMILES

CCC(C1=CC=CC=C1)C1=C(O)C2=C(OC1=O)C=CC=C2

Source: Drug Bank

Average Molecular Weight

280.3178

Source: Drug Bank

Monoisotopic Molecular Weight

280.109944378

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
ALB (source: Drug Bank)
ORM1 (source: Drug Bank)
VKORC1 (source: Drug Bank)
No related drugs are available.

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
May Prevent
Contraindicated With

Publications related to phenprocoumon: 21

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon. The New England journal of medicine. 2013. Verhoef Talitha I, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Evaluation of the effect of SNPs in CYP3A4 and CYP4F2 on the stable phenprocoumon and acenocoumarol maintenance dose. Journal of thrombosis and haemostasis : JTH. 2013. van Schie Rianne M F, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis. Clinical pharmacology and therapeutics. 2012. Danese E, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters. European journal of clinical pharmacology. 2011. Geisen Christof, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes. Pharmacogenetics and genomics. 2011. Teichert Martina, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Impact of pharmacokinetic (CYP2C9) and pharmacodynamic (VKORC1, F7, GGCX, CALU, EPHX1) gene variants on the initiation and maintenance phases of phenprocoumon therapy. Thrombosis and haemostasis. 2011. Luxembourg Baete, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood. 2010. Nowak-Göttl Ulrike, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement. European journal of clinical pharmacology. 2010. Puehringer Helene, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. European journal of clinical pharmacology. 2010. Cadamuro Janne, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Pharmacogenetic characteristics of patients with complicated phenprocoumon dosing. European journal of clinical pharmacology. 2009. Werner D, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Prediction of the effects of genetic polymorphism on the pharmacokinetics of CYP2C9 substrates from in vitro data. Pharmaceutical research. 2009. Kusama Makiko, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thrombosis and haemostasis. 2008. Beinema Maarten, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Evidence for a pharmacogenetic adapted dose of oral anticoagulant in routine medical practice. European journal of clinical pharmacology. 2008. Becquemont Laurent. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clinical pharmacology and therapeutics. 2007. Schalekamp T, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Contribution of CYP2C9 to variability in vitamin K antagonist metabolism. Expert opinion on drug metabolism & toxicology. 2006. Daly Ann K, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS medicine. 2005. Reitsma Pieter H, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clinical pharmacology and therapeutics. 2004. Schalekamp Tom, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics. 2004. Kirchheiner Julia, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics. 2004. Visser Loes E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Determination of bleeding risk using genetic markers in patients taking phenprocoumon. European journal of clinical pharmacology. 2003. Hummers-Pradier Eva, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00946
ChEBI:
50438
PubChem Compound:
9908
PubChem Substance:
153131
BindingDB:
768
Therapeutic Targets Database:
DAP000771

Clinical Trials

These are trials that mention phenprocoumon and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.