Impact of P-glycoprotein on clopidogrel absorption

Taubert, Dirk; Beckerath, Nicolas von; Grimberg, Gundula; Lazar, Andreas; Jung, Norma; Goeser, Tobias; Kastrati, Adnan; Schömig, Albert; Schömig, Edgar

doi:10.1016/j.clpt.2006.07.007

Cited by 385 publications

(273 citation statements)

References 36 publications

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“…5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene.…”

Section: Introductionmentioning

confidence: 99%

“…9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. 8 The genetic variant 3435C>T is associated with impaired function of the intestinal drug-efflux transporter. Previous findings suggest that individuals with the ABCB1 3435 TT genotype have reduced concentrations of the active drug metabolite 8 outcomes compared with CC and CT carriers.…”

Section: Introductionmentioning

confidence: 99%

“…8 The genetic variant 3435C>T is associated with impaired function of the intestinal drug-efflux transporter. Previous findings suggest that individuals with the ABCB1 3435 TT genotype have reduced concentrations of the active drug metabolite 8 outcomes compared with CC and CT carriers. 10,11 After intestinal absorption, biotransformation of clopidogrel into active thiol metabolite is accomplished by hepatic cytochrome P450 isoenzymes such as CYP2C19.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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Original research article INTRODUCTIONThe identification of individuals at risk of future adverse cardiovascular outcomes is important after percutaneous coronary intervention (PCI). Thus, the use of novel risk markers such as genetic polymorphisms to augment standard risk algorithms, including conventional clinical risk factors, has attracted increasing attention in recent years.Dual antiplatelet therapy with aspirin and clopidogrel is the current standard of treatment after PCI with drug-eluting stent to reduce the rate of recurrent ischemic events. 1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. Purpose: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. Methods:We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. Results:A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). Conclusions:In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors. Genet Med

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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“…The ABCB1 C3435T SNP appears only to affect patients treated with clopidogrel when they are homozygous -3435TT -for the SNP. This was noticed after a single dose of 300 and 600 mg (Taubert et al, 2006). Once the dosage had been increased to 900 mg the reduced clopidogrel response appeared to be overcome.…”

Section: Clopidigrel Pharmacokineticsmentioning

confidence: 96%

“…Pgp is responsible for the transport of a wide range of compounds across membranes. Following absorption, clopidogrel, which is a prodrug, requires several bioactivation steps largely mediated by CYP450 enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5) to form an active metabolite (Kazui et al, 2010;Kurihara A, 2005;Taubert et al, 2006). This active metabolite binds irreversibly to the to the P2RY 12 platelet surface receptor, inhibiting adenosine diphosphate (ADP) inducing platelet aggregation (Hollopeter et al, 2001;Savi et al, 2000).…”

Section: Clopidogrelmentioning

confidence: 99%

Cardiovascular pharmacogenetics

Myburgh

Hochfeld

Dodgen

et al. 2012

Pharmacology & Therapeutics

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Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (drug metabolising enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimising drug toxicity and optimizing drug efficacy in cardiovascular medicine.

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Clinical, Angiographic, and Genetic Factors Associated With Early Coronary Stent Thrombosis

Cayla

Hulot²,

O’Connor³

et al. 2011

JAMA

190

131

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Impact of P-glycoprotein on clopidogrel absorption

Abstract: Clopidogrel absorption and thereby active metabolite formation are diminished by P-gp-mediated efflux and are influenced by the MDR1 C3435T genotype.

Cited by 385 publications

References 36 publications

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Cardiovascular pharmacogenetics

Clinical, Angiographic, and Genetic Factors Associated With Early Coronary Stent Thrombosis

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