Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation

Tai, Ting; Mi, Qiong‐Yu; Ji, Jin-Zi; Yin, Qian; Pan, Yuqin; Zhang, Meng-Ran; Huang, Beibei; Xie, Hong‐Guang

doi:10.1097/fjc.0000000000000428

Cited by 13 publications

(16 citation statements)

References 34 publications

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“…A pilot clinical research study indicated that patients with low ABCC3 mRNA expression would respond well to clopidogrel and vice versa (Luchessi et al, 2012). Consistent with this finding, we observed that the Abcc3 knockout (KO) mice exhibit an enhanced platelet response to clopidogrel due to increased CAM formation when compared with wild-type (WT) mice (Tai et al, 2016).…”

Section: Introductionsupporting

confidence: 81%

“…The concentrations of clopidogrel, CAM, CLP-C, and CLP-G in plasma and liver tissue as well as piroxicam (IS) were determined by the validated LC-MS/ MS method as described elsewhere (Tai et al, 2016;Yin et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…Despite its widespread use in clinical settings as an antiplatelet drug (Xie et al, 2011;Saeed et al, 2017), clopidogrel continues to draw attention worldwide. Previous studies demonstrated that clopidogrel undergoes extensive metabolism in the liver (Kazui et al, 2010;Xie et al, 2011;Zhu et al, 2013;Savu et al, 2016;Tai et al, 2016). In the human body, ;85% of ingested clopidogrel is rapidly hydrolyzed to clopidogrel carboxylate (CLP-C, an inactive carboxylic acid form), an immediate metabolite, by hepatic carboxylesterase 1 (Zhu et al, 2013); the remaining 15% is metabolized to clopidogrel active metabolite (CAM) by multiple cytochrome P450-mediated two-step oxidative pathways in the liver (Savi et al, 1992(Savi et al, , 2000Kazui et al, 2010;Xie et al, 2011Xie et al, , 2017.…”

Section: Introductionmentioning

confidence: 99%

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Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood

Tai

Huang

et al. 2017

Drug Metab Dispos

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Clopidogrel acyl glucuronide (CLP-G) is a major phase II metabolite of clopidogrel generated in the liver for further excretion into urine; however, it is unclear whether CLP-G transports from hepatocytes into blood. Because multidrug resistance-associated protein 3 (MRP3) is predominantly expressed in the sinusoidal side of hepatocytes and preferentially transports glucuronide conjugates of drug metabolites from hepatocytes into bloodstream, we hypothesized that MRP3 could be such an efflux transporter for CLP-G. In this study, we compared the liver-to-plasma ratios of clopidogrel and its metabolites (including CLP-G) between (ATP-binding cassette, subfamily C, member 3) knockout (KO) and wild-type (WT) mice. We also evaluated the ATP-dependent uptake of clopidogrel and CLP-G as well as estradiol-17-d-glucuronide into human recombinant MRP3 inside-out membrane vesicles in the presence or absence of ATP. The results indicated that the liver-to-plasma ratio of CLP-G was 11-fold higher in KO mice than in WT mice, and that uptake of CLP-G (1 or 10 M each) into the membrane vesicles was 11.8- and 3.8-fold higher in the presence of ATP than in the presence of AMP, respectively. We conclude that Mrp3 transports CLP-G from the hepatocytes into blood in an ATP-dependent manner.

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Section: Introductionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood

Tai

Huang

et al. 2017

Drug Metab Dispos

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“…immediate derivatization with MPB as described elsewhere (Tai et al, 2016;. Plasma was separated after centrifugation at 1,960× g for 10 min and stored at −80°C until analysis.…”

Section: What Is the Clinical Significancementioning

confidence: 99%

“…The samples were prepared as described previously (Jia et al, 2018;Tai et al, 2016; with slight modifications. In brief, an aliquot of 10 μl plasma was spiked with 100-μl acetonitrile (containing 10-ng•ml −1 piroxicam as IS) and then vortex-mixed for 3 min for protein precipitation.…”

Section: Sample Preparationmentioning

confidence: 99%

Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine

Jia

Zhou

Tai

et al. 2019

British J Pharmacology

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Background and Purpose: Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. There is limited evidence indicating that exogenous IL-10 suppresses CYP3A4 activity in healthy subjects and that IL-10 knockout (KO) mice exhibit increased clopidogrel bioactivation compared with wild-type (WT) mice. In this study, we sought to determine whether IL-10 could play an important role in the metabolism of and platelet response to vicagrel in mice. Experimental Approach: IL-10 KO and WT mice were administered vicagrel, then their plasma H4 (active metabolite of vicagrel) concentrations were determined by LC-MS/MS, and inhibition of ADP-induced whole-blood platelet aggregation by vicagrel was assessed with an aggregometer. The mRNA and protein levels of several relevant genes between IL-10 KO and WT mice were measured by qRT-PCR and Western blots, respectively. Intestinal Aadac protein levels were measured in IL-10 WT mice injected i.p. with vehicle control, Stattic, or BAY 11-7082. Key Results: Compared with WT mice, IL-10 KO mice exhibited significantly increased plasma levels of H4 and enhanced platelet responses to vicagrel, as well as significantly higher mRNA and protein levels of arylacetamide deacetylase (Aadac) in the intestine. In WT mice, STAT3, not NF-κB, mediated Aadac expression in the intestine. Conclusions and Implications: IL-10 suppresses metabolic activation of vicagrel through down-regulation of Aadac in mouse intestine in a STAT3-dependent manner and, consequently, attenuates platelet responses to vicagrel, suggesting that the antiplatelet effect of vicagrel may be modulated by changes in plasma IL-10 levels in relevant clinical settings. 1 | INTRODUCTION A large number of relevant studies have demonstrated that inflammatory cytokines are involved in the whole process of atherosclerosis, due to their excessive generation and uninterrupted release in response to inflammatory stimuli (Ramji & Davies, 2015), and that inflammation plays a critical role in the pathogenesis and progression

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P-glycoprotein deficiency enhances metabolic activation of and platelet response to clopidogrel through marked up-regulation of Cyp3a11 in mice: Direct evidence for the interplay between P-glycoprotein and Cyp3a

Jiang

et al. 2021

Biochemical Pharmacology

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Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation

Cited by 13 publications

References 34 publications

Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood

Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood

Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine

P-glycoprotein deficiency enhances metabolic activation of and platelet response to clopidogrel through marked up-regulation of Cyp3a11 in mice: Direct evidence for the interplay between P-glycoprotein and Cyp3a

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