Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel

Savi, Pierre; Herbert, Jean‐Marc; Pflieger, A M; Dol, Frédérique; Delebassee, Denis; Combalbert, Jean; Defreyn, G.; Maffrand, Jean‐Pierre

doi:10.1016/0006-2952(92)90445-o

Cited by 200 publications

(146 citation statements)

References 9 publications

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

“…[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. 8 The genetic variant 3435C>T is associated with impaired function of the intestinal drug-efflux transporter.…”

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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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%

“…[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. 8 The genetic variant 3435C>T is associated with impaired function of the intestinal drug-efflux transporter.…”

Section: Introductionmentioning

confidence: 99%

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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“…Clopidogrel does not, by itself, exhibit direct antiaggregant activity in vitro. Indeed, in vivo studies have demonstrated that clopidogrel has to undergo hepatic metabolization to obtain an active metabolite (53). This active metabolite (Act-Met) has been isolated, and its structure has been elucidated (54).…”

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confidence: 99%

The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts

Savi

Zachayus

Delesque-Touchard

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

279

221

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P2Y12, a G protein-coupled receptor that plays a central role in platelet activation has been recently identified as the receptor targeted by the antithrombotic drug, clopidogrel. In this study, we further deciphered the mechanism of action of clopidogrel and of its active metabolite (Act-Met) on P2Y12 receptors. Using biochemical approaches, we demonstrated the existence of homooligomeric complexes of P2Y12 receptors at the surface of mammalian cells and in freshly isolated platelets. In vitro treatment with Act-Met or in vivo oral administration to rats with clopidogrel induced the breakdown of these oligomers into dimeric and monomeric entities in P2Y12 expressing HEK293 and platelets respectively. In addition, we showed the predominant association of P2Y12 oligomers to cell membrane lipid rafts and the partitioning of P2Y12 out of rafts in response to clopidogrel and Act-Met. The raft-associated P2Y12 oligomers represented the functional form of the receptor, as demonstrated by binding and signal transduction studies. Finally, using a series of receptors individually mutated at each cysteine residue and a chimeric P2Y12͞P2Y13 receptor, we pointed out the involvement of cysteine 97 within the first extracellular loop of P2Y12 in the mechanism of action of Act-Met. mechanism of action ͉ platelet ͉ antiaggregant M any G protein-coupled receptors (GPCRs) have been shown to assemble as homodimers, heterodimers, as well as larger oligomers (1, 2). The existence of such oligomeric entities raises questions as to their functional consequences as well as their physiological relevance. Heterologous expression systems have provided a variety of answers concerning ligand-dependent regulation of GPCR oligomeric states. Ligand binding, depending on the GPCR studied, can promote (3-10) or inhibit (11-13) dimer formation, as well as having no effect on preexisting constitutive homo-or heterodimers (14-25). The fact that heterodimerization may alter the pharmacological properties of a GPCR along with its internalization and signal transduction behavior is of critical importance (26, 27).Clustering, even for nonheptahelical receptors, now appears as a common feature of cell signaling. Specialized structures such as clathrin-coated pits, caveolae, and lipid rafts contain high concentrations of signaling molecules. Rafts represent dynamic assemblies of proteins and lipids, mostly sphingolipids and cholesterol (28,29). Proteins such as glycophosphatidylinositol-anchored proteins, nonreceptor tyrosine kinases, G␣ subunits of heterotrimeric G proteins, and palmitoylated proteins appear to localize to these microdomains (30). In addition, recent studies have shown that partitioning of proteins in and out of rafts can depend on their state of activation or dimerization (31-33). A variety of GPCR have also been identified in caveolae or rafts. These include ␣ and ␤-adrenergic receptors (34, 35), adenosine A1 receptor (36), angiotensin II type 1 receptor (37), muscarinic receptor (38), EDG1 receptor (39), bradykinin B1 and B2 receptor...

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“…This possibility is supported by the time-dependence of platelet inhibitory actions of clopidogrel in their study. In rats, Savi et al [47] reported that clopidogrel (40 mg kg −1 ) was less effective in hepatectomized rats as compared to normal control rats. In addition, clopidogrel did inhibit platelet aggregation in isolated, blood-perfused rat livers.…”

Section: Discussionmentioning

confidence: 99%

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Özsavcı¹,

Şener²,

Oba³

et al. 2010

Turk J Hematol

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Objective: We aimed to detect novel in vitro effects of clopidogrel on platelets by assessment of the following parameters: malondialdehyde, glutathione, nitrite, aggregation response, and expressions of P-selectin, fibrinogen, apolipoprotein A1, apolipoprotein B, and phosphatidylserine. Materials and Methods: Platelets were obtained from healthy (n: 9) and hyperlipidemic (n: 9) volunteers. Expressions of P-selectin, fibrinogen, apolipoproteins A1/B and phosphatidylserine with and without clopidogrel were assayed by flow cytometry. Malondialdehyde, glutathione, aggregation and nitrite levels were also assayed. Results: Without clopidogrel, the baseline values of platelet aggregation, malondialdehyde, and expressions of P-selectin, fibrinogen and phosphatidylserine were significantly higher, whereas nitrite and expression of apolipoproteins A1/B were significantly lower in hyperlipidemics than in the healthy group. In both groups, clopidogrel significantly reduced aggregation and expression of fibrinogen, but it elevated nitrite levels. Clopidogrel significantly decreased P-selectin and phosphatidylserine expression and malondialdehyde but increased expressions of apolipoproteins A1/B only in hyperlipidemics. Conclusion: It seems that clopidogrel has some new in vitro antiplatelet effects. The present study is a basic in vitro study to suggest new insights into the effects of clopidogrel on platelet functions. Özet Amaç: Klopidogrelin trombositler üzerinde yeni in vitro etkilerini tayin etmek: Malondialdehit, glutatyon, nitrit, aggregasyon cevabı, P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları. Yöntem ve Gereçler: Sağlıklı (n: 9) ve hiperlipidemik (n: 9) olgulardan trombositler elde edildi. Klopidogrelli ve klopidogrelsiz trombositlerde P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları flow sitometre ile tayin edildi. Malondialdehit, glutatyon, aggregasyon ve nitrit seviyeleri de tayin edildi. Bulgular: Klopidogrel yokluğunda, hiperlipidemililerde kontrollere göre trombosit agregasyonu, malondialdehit, P-Selektin, fibrinojen ve fosfatidilserin ekspresyonunun başlangıç değerleri yüksek; bununla birlikte nitrit, apolipoprotein A1 ve apolipoprotein B ekspresyonlarınınki ise daha düşüktü. Her iki grupta, klopidogrel anlamlı düzeyde aggregasyonu ve fibrinojen ekspresyonunu azalttı, fakat nitrit seviyelerini artırdı. Klopidogrel sadece hiperlipidemililerde P-selektin ve fosfatidilserin ekspresyonunu ve malondialdehiti azalttı ancak apolipoprotein A1 ve apolipoprotein B ekspresyonlarını artırdı.

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Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel

Cited by 200 publications

References 9 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

The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

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