Genetic and environmental risk factors for oral anticoagulant overdose

Verstuyft, Céline; Robert, Annie; Morin, Sandrine; Loriot, Marie‐Anne; Flahault, Antoine; Beaune, Philippe; Funck‐Brentano, Christian; Jaillon, Patrice; Becquemont, Laurent

doi:10.1007/s00228-002-0538-2

Cited by 46 publications

(32 citation statements)

References 35 publications

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“…Four studies [48], [68], [100], [103] investigated this association. Three were excluded: one [103] since it was a case-control study, with cases defined as those with high INR and controls as those with INR within the normal range, and therefore did not represent the general warfarin patient population, and two [68], [100] because insufficient data were reported.…”

Section: Resultsmentioning

confidence: 97%

“…Of these, only one [51] provided justification, whilst another [36] chose to assume a dominant mode on the basis that the number of mutant-types was small. For the remaining 26 studies [17], [23], [27], [31], [32], [37], [39], [40], [42], [44], [49], [50], [52], [63], [67], [69], [74], [77], [78], [84], [103], [104], [112]–[115] there is a risk of within-study selective reporting where several analyses under different modes of inheritance may have been conducted with only the most statistically significant being reported. The same is true for eight studies [22], [35], [70], [89], [95], [96], [116], [117] that compared various combinations of genotype groups with no apparent justification.…”

Section: Resultsmentioning

confidence: 99%

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Influence of CYP2C9 and VKORC1 on Patient Response to Warfarin: A Systematic Review and Meta-Analysis

et al. 2012

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BackgroundWarfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent.Methodology/Principal FindingsA comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7–1.5) and 2.3 (1.6–3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4–1.3) and 1.5(1.1–1.8)mg/day more in asians and between 1.5(0.7–2.2) and 3.1(2.7–3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches.Conclusions/SignificanceGenetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Influence of CYP2C9 and VKORC1 on Patient Response to Warfarin: A Systematic Review and Meta-Analysis

et al. 2012

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“…Indeed, AC metabolism is influenced by a number of pathologic, physiologic, and environmental factors. 2,24 In a previous study, 12 we have shown that body weight and one CYP2C9 haplotype accounted for about 19% of the variability in the anticoagulant effect of AC. To improve and extend these findings, the VKORC1 gene was also studied.…”

Section: Discussionmentioning

confidence: 99%

“…This interindividual variability is known to depend on environmental factors, but a genetic influence has also been demonstrated. [2][3][4][5][6] The cytochrome P450 2C9 (CYP2C9) is the main enzyme responsible for the hepatic metabolism of oral anticoagulants such as AC and warfarin. The CYP2C9 has been demonstrated to be polymorphic, and its genetic variability has been shown to be associated with variations in the levels of enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity

Bodin

Verstuyft

Trégouët

et al. 2005

Blood

328

238

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The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: ؊4931T>C, ؊4451C>A, ؊2659G>C, ؊1877A>G, ؊1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the ؊1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 ؊1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy. (Blood. 2005;106:135-140)

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“…The G2677T/A and C3435T polymorphisms have been associated with nearly a 2-fold decreased expression of P-gp in duodenal biopsy samples (Hoffmeyer et al, 2000) and altered pharmacokinetics [higher plasma levels or higher area under plasma concentration-time curve (AUC)] of several P-gp substrates, including digoxin (Hoffmeyer et al, 2000;Kurata et al, 2002;Johne et al, 2002;Verstuyft et al, 2003), cyclosporine (Chowbay et al, 2003;Yates et al, 2003) and tacrolimus (Anglicheau et al, 2003;Yamauchi et al, 2002;Zheng et al 2003). However, contradictory results have also been noted as these polymorphisms did not significantly alter the pharmacokinetics of digoxin Horinouchi et al 2002;Sakada et al 2001), cyclosporine (Anglicheau et al 2004;Haufroid et al 2004;Hesselink et al 2003;Kuzuya et al 2003;Von Ahsen et al 2001), fexofenadine (Drescher et al, 2002;Kim et al, 2001;) or tacrolimus (Goto et al, 2002;Haufroid et al, 2004).…”

Section: Abcb1 Gene Encoded Multi-drug Resistance Protein or P-glycopmentioning

confidence: 99%

The Emerging Importance of Transporter Proteins in the Psychopharmacological Treatment of the Pregnant Patient

Wang

Newport

Stowe

et al. 2007

Drug Metabolism Reviews

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P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins have physiological functions in placental tissue. Several antidepressants, antipsychotics, and anti-epileptic drugs have been found to be substrates of P-glycoprotein and other transporters. The extent that drugs pass through the placental barrier is likely influenced by drug transporters. The rational choice of psychoactive drugs to treat mental illness in women of child-bearing age should incorporate knowledge of both drug disposition as well as expected pharmacologic effects. This review summarizes the current data on drug transporters in the placental passage of medications, with a focus on medications used in clinical psychopharmacology.

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Genetic and environmental risk factors for oral anticoagulant overdose

Cited by 46 publications

References 35 publications

Influence of CYP2C9 and VKORC1 on Patient Response to Warfarin: A Systematic Review and Meta-Analysis

Influence of CYP2C9 and VKORC1 on Patient Response to Warfarin: A Systematic Review and Meta-Analysis

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity

The Emerging Importance of Transporter Proteins in the Psychopharmacological Treatment of the Pregnant Patient

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