P-glycoprotein: a clue to vitamin K antagonist stabilization

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From: Pharmacogenomics(Vol. 16, Issue 2)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 4,804 words
Lexile Measure: 1520L

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Author(s): Liliane Gschwind aff1 aff2 , Victoria Rollason [*] aff1 , Françoise Boehlen aff3 , Michela Rebsamen aff4 , Christophe Combescure aff5 , Alain Matthey aff1 , Pascal Bonnabry aff2 aff6 , Pierre Dayer aff1 , Jules Alexandre Desmeules aff1

Keywords:

ABCB1 ; acenocoumarol; drug transporter; gene polymorphism; pharmacogenetics; P-glycoprotein; vitamin K antagonists

Acenocoumarol is a vitamin K antagonist (VKA) used in some European countries and the most frequently prescribed oral anticoagulant in the University Hospitals of Geneva (Switzerland). As warfarin, acenocoumarol is mainly used for the prevention and the treatment of thromboembolic disorders. VKAs have a narrow therapeutic index and are characterized by a large interpatient variability in the dose required to achieve target anticoagulation. These characteristics make VKAs treatment difficult to handle and require frequent controls of the anticoagulant effect by measuring the international normalized ratio (INR) to avoid bleeding and thrombotic complications, which are the most common expected adverse drug reactions with this class of drugs [1 ].

Although all VKAs share the same pharmacological properties and chemical structure, their pharmacokinetic properties differ significantly. CYP2C9 is the main enzyme responsible for the metabolism of acenocoumarol, CYP1A2 and CYP2C19 being minor metabolic pathways [2 ]. Unlike warfarin, acenocoumarol is not metabolized by CYP3A4 [3 ].

Several factors including age, sex, comorbidities and concomitant drugs have been shown to contribute to the variability in the anticoagulant effect of VKAs [4,5 ]. There is also extensive evidence that a large part of their variability can be explained by genetic factors especially polymorphisms in the VKORC1 gene coding for the vitamin K epoxide reductase (the main target for VKAs) and the CYP2C9 gene [6-8 ]. Although, the large majority of pharmacogenetic studies refer to warfarin, CYP2C9 and VKORC1 polymorphisms have also been reported to have an impact on acenocoumarol treatment. These polymorphisms have been associated with lower dose requirements, higher frequency of overanticoagulation and bleeding and an unstable anticoagulant response particularly at the initiation of therapy [ 9-11 ].

P-glycoprotein (P-gp), a potent efflux pump, is expressed in the apical membrane of many secretory cells localized in the intestine, liver, kidney, blood-brain barrier and placenta were the normal function involves the excretion of drugs [12 ]. P-gp also plays a critical role in drug disposition. P-gp is encoded by the ABCB1 gene previously called MDR1 , for which more than 100 SNPs have been identified in the coding region [ 13 ]. Three of these SNPs are common in most ethnic groups and have demonstrated a strong linkage disequilibrium: the synonymous transition at nucleotide c.3435C[greater than]T (Ile1145Ile) in exon 26, the nonsynonymous triallelic transition c.2677G[greater than]T/A resulting in two possible amino acid changes (p.Ala893Ser/Thr) in exon 21 and the synonymous transition c.1236C[greater than]T (p.Gly411Gly) in exon 12 [14 ]. The impact of these polymorphisms on ABCB 1 mRNA levels, P-gp expression or activity in various tissues, as well as on the pharmacokinetics of different substrates remains discussed [15 ]. Regarding VKAs, a few studies have shown preliminary evidence that P-gp could contribute to warfarin or acenocoumarol sensitivity but results remain conflicting [16-20 ].

The aim...

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Gale Document Number: GALE|A413526795