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University of Groningen Pharmacogenetic Differences University of Groningen Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon Beinema, Maarten; Brouwers, Jacobus R. B. J.; Schalekamp, Tom; Wilffert, Bob Published in: Thrombosis and Haemostasis DOI: 10.1160/TH08-04-0116 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2008 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Beinema, M., Brouwers, J. R. B. J., Schalekamp, T., & Wilffert, B. (2008). Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thrombosis and Haemostasis, 100(6), 1052-1057. https://doi.org/10.1160/TH08-04-0116 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 ©2008 Schattauer GmbH,Stuttgart Review Article Pharmacogenetic differencesbetween warfarin,acenocoumarol andphenprocoumon Maarten Beinema1;JacobusR.B.J.Brouwers2;Tom Schalekamp3;Bob Wilffert2 1ThrombosisCentre,Deventer Hospital,Deventer,The Netherlands; 2Department of Pharmacotherapy and Pharmaceutical Care,University of Groningen, Groningen, The Netherlands; 3Division of Pharmacoepidemiologyand Pharmacotherapy,Faculty of Science,UtrechtInstitute forPharmaceutical Sciences, Utrecht University,Utrecht, The Netherlands Summary Coumarin oral anticoagulant drugs have proven to be effective VKAs. TheCYP2C9 polymorphismisassociated with delayed forthe prevention of thromboembolic events.World-wide,war- stabilisationfor coumarin anticoagulants.Theeffects of CYP2C9 farinisthe most prescribeddrug.In Europe,acenocoumarol and polymorphisms on the pharmacokinetics and anticoagulant re- phenprocoumonare also administered.Ye tithas been proven sponse areleast pronounced in the case of phenprocoumon. In that variant allelesofthe VKORC1and CYP2C9genotypes in- the long term,patientsusing phenprocoumon have moreoften fluence the pharmacokineticsand pharmacodynamics of these international normalisedratio (INR) valuesinthe therapeutic drugs. Thecombination of thesetwo variant genotypesisa range,requiring fewermonitoringvisits.This leadsustocon- major cause of theinter-individual differencesincoumarin anti- clude that in theabsence of pharmacogenetic testing, phenpro- coagulantdrugdosage.Individualswho test positive forboth coumon seemspreferable foruse in long-term therapeutic anti- variantgenotypes areatincreasedriskofmajor bleeding.The coagulation. Pharmacogenetic testing before initiating coumarin impact of the CYP2C9 andVKORC1genotypeismost significant oral anticoagulants mayadd to the safety of all coumarin antico- duringthe initialperiod of coumarin anticoagulant therapy.The agulants especiallyinthe elderlyreceiving multiple drugs. effect ofVKORC1allelic variants is relativelysimilarfor all three Keywords Clinical trials,oral anticoagulants,pharamacogenetics,phar- macodynamics ThrombHaemost 2008; 100: 1052–1057 Introduction The major side effect of VKAsismajor bleeding,with re- ported incidences of 1.5to5.0 per 100 patient-years (2,3). The Coumarinanticoagulants, also called vitamin Kantagonists incidenceofboth bleeding and thromboembolic eventsincreases (VKAs),are effective in the prevention of venous and arterial sharplywith advanced age. Therisk of over-and under-coagu- thromboembolism (1).VKAs suppress theregeneration of the lation in patients taking VKAsisassociatedwith drug-VKAs in- reduced formofvitamin Kbyinhibiting vitamin Kepoxide re- teractions, food-VKAs interactions, and disease-VKAs interac- ductase. The vitamin Kcycle regenerates reducedvitamin K1 tions.Alcoholconsumption, liverdisease, and other unknown from its epoxide.. Reduced vitamin Kisacofactor for post-trans- factorsalso influenceoptimal dailydosages. Other inter-individ- lational gamma-carboxylation of glutamic acidresiduesonsev- ual variationsthat affect predicting optimal dailydosagesin- eral proteins fornormal haemostasis. This resultsinnegatively clude pharmacogenetic predisposition, age and patient obesity, charged gamma-carboxyglutamateson factorsII, VII, IX, and X, whichcorresponds to the amount of coumarin anticoagulants whichbind to calcium cations and thentoplateletphospholipid requiredfor initiation of therapy(4–6). This explains whyoral membranes. Gamma-carboxylation is also requiredfor the de- anticoagulants have asmall therapeutic window, and the stability velopment of othertissues. VKAs also inhibit the gamma-car- of anticoagulant therapycan be easilydisturbed. boxylation of anticoagulant proteins C, S, Z, and osteocalcin. Both safety (primarily risk of bleeding)and effectiveness of VKAsinhibition of clotting factor activity is their main phar- VKAstherapyrelates to blood international normalised ratio macologic effect.This is responsible for VKAsability to inhibit (INR) values(7). Monitoring of INRand dose adjustments of clot formation. coumarin anticoagulants arefrequently required. Futhermore, Correspondence to: Received: April 4, 2008 MaartenBeinema, MD Accepted after major revision: September14, 2008 DeventerHospital Thrombosis Centre PO box5001, 7400GCDeventer,The Netherlands Prepublished online: November 13, 2008 Te l.: +31570 646286, Fax: +31 570 646287 doi:10.1160/TH08-04-0116 E-mail: [email protected] 1052 Beinema et al.Pharmacogeneticdifferencesbetween warfarin, acenocoumaroland phenprocoumon pharmacogenetics,the fieldofresearch describing the influence This complex recycles reduced vitamin K, whichisessential for of variationsofDNA characteristics on drug response,plays an the post-translationalgamma-carboxylation of vitamin K–de- important roleinthe safety and effectiveness of VKAs. pendent clotting factorsII(prothrombin),VII, IX,and X, and of Warfarin is the VKAs drug of choiceinmost countries. Ye t proteins C, Sand Z. acenocoumarol and phenprocoumon are used in many European The impact of other enzymes polymorphisms, likeGGCX countries, includingThe Netherlands and Germany. Several re- (gamma-glutamyl carboxylase), on coumarin anticoagulant dose viewsand researchpapersonthe pharmacogenetic influences of finding has beenexamined,but thereare no significant results. warfarin are available(8, 9). Comparatively systematic informa- tion on the pharmacogenetic influences of acenocoumarol and Warfarin phenprocoumon is scarce. In this review,wefocus on the phar- macogeneticsofphenprocoumon and acenocoumarol, compar- Warfarin is aracemate, with S-warfarinbeing three timesaspo- ing these drugs with the pharmacogeneticsofwarfarin. We also tent as R-warfarin. TheS-enantiomerinwarfarinispredomi- exploredthese drugs’ relevance to therapeutic choices. nantlyresponsible for the anticoagulant effect.When adminis- We performed the literaturesearch in EMBASE and Medline tered orally, warfarin is completelyabsorbedand 99% is bound (PUBMED)from 1995 to June2008. We includedstudieswith to albumin in the plasma. The liverabsorbs the free warfarin originaldataonpharmacogeneticsofphenprocoumon and ace- where it exerts its anticoagulant effect andis metabolized by sev- nocoumarol. Data from warfarin reviewsand additional relevant eral CYP-enzymes. papers not included in the cited reviews were alsoincluded. Ye tfrom aclinical standpoint, R-warfarinisthe most active Search words and termsincluded: pharmacogeneticsand/or anticoagulant. This is becauseCYP2C9metabolisesS-warfarin pharmacogenomics; acenocoumarol;phenprocoumon; in the first-pass-effect very efficiently.CYP2C9convertsthe CYP2C9 and/or genotype and /or polymorphism;VKORC1; S-enantiomer to 6- and 7-hydroxy-warfarin, whichiseventually warfarin and review;and coumarin anticoagulants. excreted in the bile.Incomparison, CYP1A1, CYP1A2, and CYP3A4 metabolize R-enantiomer into an inactive alcohol- metabolite excreted in the urine. Cytochrome P4502C9 andVKORC1 and other Patients with eitheraCYP2C9*2 or CYP2C9*3 polymor- genetic variants phismhaveimpaired metabolismofthe more active enantiomer S-warfarinwhen comparedtopatients whoare homozygous for CytochromeP450 (CYP) is agroupofhepatic microsomal the wild-typeallele CYP2C9*1(11). The unbound S-warfarin enzymes thatact as monooxygenases of endobiotics (steroid hor- clearance is about two- to three-fold lowerinheterozygouscar- mones, fatty acids derivates, and vitamins) and xenobiotics riers of the CYP2C9*3 allele and about 10-fold lowerinhomozy- (drugs, pollutants, and carcinogens).The abbreviation CYP,fol- gous carriers (12). lowedbyanumber,acapitalletterand anothernumber (e.g. In vivo,these twoCYP2C9SNPshavebeen associatedwith CYP2D6, CYP3A4, CYP2C9), designates an individual enzyme
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