Contribution of CYP2C9 to variability in vitamin K antagonist metabolism

Abstract

CYP2C9 is the third most important cytochrome P450 (CYP) in terms of number of drugs metabolised. A considerable amount of information on this isoform is now available with respect to its structural biology, the mechanisms by which it can be induced and the existence of a range of variant alleles, which are often functionally significant. CYP2C9 makes a very important contribution to metabolism of vitamin K antagonist anticoagulants, and is the main oxidising enzyme for S-warfarin and S-acenocoumarol as well as contributing to phenprocoumon metabolism. A large number of studies have now shown that CYP2C9 genotype predicts dose requirement for both warfarin and acenocoumarol, with a possible contribution for phenprocoumon. Patients with variant alleles are likely to require a lower dose and may be at risk of overcoagulation and resultant bleeding, especially during the induction phase of therapy. Although CYP2C9 genotype is clearly a predictor of vitamin K antagonist dose requirement, especially in Caucasian populations in whom variant alleles are common, a number of recent studies have shown that age, genotype for the gene encoding the target gene vitamin K epoxide reductase and concomitant drugs are equally important factors in determining dose. There is a need for prospective studies to assess the value of predicting dose requirement on the basis of all these factors, including the CYP2C9 genotype.

Influence ofCYP2C9andVKORC1Polymorphisms on Warfarin and Acenocoumarol in a Sample of Lebanese People

“…This means that, in our population, the CYP2C9 effect was mostly driven by the CYP2C9*3 genetic polymorphism. These results are in concordance with the literature for acenocoumarol 31,32 but not for warfarin, which has been consistently shown to be significantly affected by the CYP2C9*2 polymorphism as well. 33 It is possible that, because warfarin is not as commonly prescribed as acenocoumarol in Lebanon, there was not enough power to show significant results with CYP2C9*2.…”

Dependency of phenprocoumon dosage on polymorphisms in the VKORC1 and CYP2C9 genes

“…CYP2C9, a cytochrome P450, is the main oxidizing enzyme for warfarin [4] and acenocoumarol [5] and also contributes to the phenprocoumon metabolism [6,7]. Patients with CYP2C9 polymorphisms metabolize coumarins slower, which is why they are likely to require a lower dose, may be at risk of over-anticoagulation, and are twice as likely to have a clinical or laboratory adverse event unless their initial coumarin dosage is reduced [8].…”

“…Patients with CYP2C9 polymorphisms metabolize coumarins slower, which is why they are likely to require a lower dose, may be at risk of over-anticoagulation, and are twice as likely to have a clinical or laboratory adverse event unless their initial coumarin dosage is reduced [8]. In the presence of CYP2C9 polymorphisms, the dosage of phenprocoumon to achieve therapeutic INR values appears to be lower compared with warfarin or acenocoumarol [6]. Since metabolization of phenprocoumon is less influenced by CYP2C9 polymorphisms as compared with other OAC, some authors regard phenprocoumon as a valuable alternative for therapeutic OAC of patients expressing a CYP2C9 polymorphism [9].…”

“…However, it is not known if determination of the CYP2C9 genotype for dose adjustment before starting treatment with phenprocoumon will reduce the increased risk of major bleeding events [10]. Though CYP2C9 polymorphisms seem to influence VKA dosage for therapeutic OAC, particularly in Caucasians, in whom these polymorphisms are more common than in other ethnia, it should not be neglected that age, concomitant drugs, hepatopathy or renal insufficiency, or the VKORC1 genotype equally determine phenprocoumon dosage [6]. Fewer studies than for CYP2C9 polymorphisms have been carried out for VKORC1 polymorphisms.…”

Risk Assessment and Communication Tools for Genotype Associations with Multifactorial Phenotypes: The Concept of “Edge Effect” and Cultivating an Ethical Bridge between Omics Innovations and Society

“…In this regard, the very recent confluence of understanding of pharmacogenomics variability in pharmacokinetic and pharmacodynamic pathways for the oral anticoagulant warfarin is a notable positive example (Cooper et al, 2008; Daly and King, 2006; Gage et al, 2008; Nakai et al, 2007; Ozdemir et al, 2008; Perini et al, 2008). Yet the future is still undecided for many of the omics biotechnology applications such as pharmacogenomics, nutrigenomics, and agrigenomics (Brown, 2003; Godard and Ozdemir, 2008; Hedgecoe, 2004; Hopkins et al, 2006; Khoury et al, 2008; McGuire and Burke, 2008; Millstone, 2000; Montpetit et al, 2006; Ozdemir and Godard, 2007).…”