CYP2B6 (IC50 = 18.2 nM); P2Y12 Receptor; CYP2C19 (IC50 = 524 nM)

根据实时PCR和其他方法，硫酸氢氯吡格雷（1.5 mM；12和24小时）以浓度和时间依赖性方式增加TRIB3和CHOP的表达。

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基因微阵列分析鉴定出79个基因在用或不用氯吡格雷处理细胞时差异表达（P<0.05，倍数变化>3）。基因本体分析显示，对应激的反应和细胞凋亡功能障碍是受影响的前10个细胞事件，当细胞用氯吡格雷处理时，内质网应激介导的凋亡途径的主要成分CHOP和TRIB3以浓度和时间依赖的方式上调。通路分析表明，在氯吡格雷处理的GES-1细胞中，多种MAPK激酶被磷酸化，但只有SB-203580（一种p38特异性MAPK抑制剂）减弱了细胞凋亡和CHOP过表达，这两者都是由氯吡格雷诱导的。 结论：在氯吡格雷诱导的胃黏膜损伤中，内质网应激反应的增强与p38 MAPK的激活有关。[3]

与载体相比，硫酸氢氯吡格雷（5 mg/kg）可有效预防血栓形成。在小鼠中，乙酰水杨酸（0.15 mg/kg）可增强氯吡格雷的抗血栓功效；在小鼠中，乙酰水杨酸（0.6 mg/kg）可以降低氯吡格雷的抗血栓作用[4]。

氯吡格雷是一种强效的抗血栓药物，可抑制ADP诱导的血小板聚集。大型临床试验的结果表明，在有症状性动脉粥样硬化病史的患者中，氯吡格雷在预防血管缺血性事件（心肌梗死、中风、血管死亡）方面优于阿司匹林。氯吡格雷的抗聚集作用归因于ADP与血小板表面嘌呤能受体结合的不可逆抑制。氯吡格雷在体外没有活性，可以被认为是肝脏中形成的活性代谢产物的前体。最近描述了这种活性代谢物的化学结构及其生物活性。血小板上已经描述了几种嘌呤能受体；已发现钙通道P2X（1）和Gq偶联的七跨膜结构域受体P2Y1不会被氯吡格雷拮抗。另一种Gi（2）偶联受体（命名为P2Y12）最近被克隆并在CHO细胞中稳定表达。这些细胞对ADP的稳定类似物（33）P-2MeS-ADP表现出很强的亲和力，其结合特征在所有点上都与血小板上观察到的特征相对应。氯吡格雷的活性代谢产物强烈抑制了（33）P-2MeS-ADP与这些细胞的结合，其效力与该化合物在血小板上观察到的效力一致。在这些转染的CHO细胞中，与血小板一样，ADP和2MeS ADP诱导腺苷酸环化酶下调，这种作用被氯吡格雷的活性代谢产物抑制。这些结果表明，该受体对应于之前称为“P2t”的血小板受体，并表明氯吡格雷的活性代谢产物以共价方式与该受体结合，从而解释了它如何阻断ADP对血小板的聚集作用[2]。

蛋白质印迹分析[3]
细胞类型： GES-1 细胞
测试浓度： 1.5 mM
孵育时间： > 12和24小时
实验结果：CHOP和TRIB3的mRNA表达水平均以浓度和时间依赖性方式上调。 CHOP 和 TRIB3 的蛋白表达水平均以浓度和时间依赖性方式上调。

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细胞凋亡分析[3]
细胞类型：胃上皮细胞 (GES-1) 细胞
测试浓度： 1.5 mM
孵育时间：24小时
实验结果：诱导胃上皮细胞凋亡．

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以GES-1细胞为模型系统，通过人类基因表达微阵列和基因本体分析评估氯吡格雷对整个基因表达谱的影响，通过实时PCR和Western blot分析确定mRNA和蛋白质表达的变化，分别通过MTT法和流式细胞仪分析测量细胞存活率和凋亡率。[3]

Animal/Disease Models: Age-matched C57BL/6J male mice weighing at least 25 g were used at 8 to 12 weeks of age[4]
Doses: 5 mg/kg
Route of Administration: Gavage treatment
Experimental Results: Clopidogrel Dramatically inhibited thrombus formation compared with vehicle. When Clopidogrel was given in combination with 0.6 mg/kg ASA, thrombi were Dramatically larger than those measured with Clopidogrel alone. In contrast, when Clopidogrel was given in combination with 0.15 mg/kg ASA, thrombi were Dramatically smaller than those in mice treated with Clopidogrel and 0.6 mg/kg ASA, and smaller than those in mice given Clopidogrel alone.

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The purpose of this study was to examine this possibility in vivo. Approach and Results- Mice were given oral acetylsalicylic acid at varying doses, oral clopidogrel (5 mg/kg body weight), or both. At doses of 0.15 and 0.6 mg/kg, acetylsalicylic acid inhibited arachidonic acid-induced platelet aggregation, but only 0.6 mg/kg acetylsalicylic acid, or higher, decreased the plasma levels of 6-keto-prostaglandin-F1α, the stable metabolite of prostacyclin. When given with clopidogrel, laser injury-induced arterial thrombi were significantly larger with the 0.6 mg/kg dose of acetylsalicylic acid than with the 0.15 mg/kg dose. Thrombi in mice treated with clopidogrel and the 0.15 mg/kg dose of acetylsalicylic acid were smaller than in mice treated with clopidogrel alone, suggesting that acetylsalicylic acid can add to the antithrombotic effect of clopidogrel but that higher doses of acetylsalicylic acid blunt the antithrombotic effect of clopidogrel. Conclusions- These findings support the use of lower, prostacyclin-preserving, doses of acetylsalicylic acid in conjunction with clopidogrel.[4]

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New Zealand white rabbits (1.9-2.7 kg) were treated orally with vehicle or clopidogrel (3 or 10 mg/kg) for three days. On the fourth day, the rabbits were anesthetized for blood collection and then euthanized. The brain was collected, and the middle cerebral arteries were isolated. We used light transmission aggregometry and pressure myography to elucidate the mechanisms of the off-target effects associated with clopidogrel treatment. We confirmed that inhibition of P2Y12 activation by clopidogrel inhibited ADP-induced platelet aggregation but had no impact on P2Y12-independent arachidonic acid- or collagen-induced platelet aggregation. Analysis of middle cerebral arteries from clopidogrel treated rabbits showed that clopidogrel did not affect P2Y4, P2Y6, and P2Y14 receptor-mediated contraction but attenuated the contractile response after P2Y2 receptor activation. Further analysis determined P2Y2-mediated constriction was endothelium-dependent. Vasoconstriction is a primary component of hemostasis, and impaired vasoconstriction can prolong bleeding. These results suggest clopidogrel inhibits the endothelial P2Y2 receptor in the middle cerebral artery, which provides a mechanistic explanation for the adverse cerebral bleeding associated with the drug.[5]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of clopidogrel during breastfeeding. The manufacturer reports that no adverse effects have been observed in breastfed infants with maternal clopidogrel use during lactation in a small number of postmarketing cases. Since no published information is available on the use of clopidogrel during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Comparison of human cytochrome P450 inhibition by the thienopyridines prasugrel, Clopidogrel, and ticlopidine. Drug Metab Pharmacokinet. 2008;23(6):412-20.

[2]. P2Y12, a new platelet ADP receptor, target of Clopidogrel.Semin Vasc Med. 2003 May;3(2):113-22.

[3]. Increased endoplasmic reticulum stress response is involved in Clopidogrel-induced apoptosis of gastric epithelial cells. PLoS One. 2013 Sep 13;8(9):e74381.

[4]. Effect of Different Doses of Acetylsalicylic Acid on the Antithrombotic Activity of Clopidogrel in a Mouse Arterial Thrombosis Model.Arterioscler Thromb Vasc Biol. 2018 Oct;38(10):2338-2344.

[5]. Clopidogrel treatment inhibits P2Y2-Mediated constriction in the rabbit middle cerebral artery [published online ahead of print, 2021 Oct 1]. Eur J Pharmacol. 2021;174545.

Clopidogrel Bisulfate is a thienopyridine with antiplatelet activity. Clopidogrel bisulfate irreversibly alters the platelet receptor for adenosine diphosphate (ADP), thereby blocking the binding of ADP to its receptor, inhibiting ADP-mediated activation of the glycoprotein complex GPIIb/IIIa, and inhibiting fibrinogen binding to platelets and platelet adhesion and aggregation. (NCI04)
A ticlopidine analog and platelet purinergic P2Y receptor antagonist that inhibits adenosine diphosphate-mediated PLATELET AGGREGATION. It is used to prevent THROMBOEMBOLISM in patients with ARTERIAL OCCLUSIVE DISEASES; MYOCARDIAL INFARCTION; STROKE; or ATRIAL FIBRILLATION.
See also: Clopidogrel (has active moiety).

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Drug Indication
Secondary prevention of atherothrombotic eventsClopidogrel is indicated in: adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from seven days until less than six months) or established peripheral arterial disease; adult patients suffering from acute coronary syndrome: non-ST-segment-elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA); ST-segment-elevation acute myocardial infarction, in combination with ASA in patients undergoing percutaneous coronary intervention (including patients undergoing a stent replacement) or medically treated patients eligible for thrombolytic/fibrinolytic therapy. In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS)Clopidogrel in combination with ASA is indicated in: Adult patients with moderate to high-risk TIA (ABCD2  score ≥4) or minor IS (NIHSS  ≤3) within 24 hours of either the TIA or IS event. Prevention of atherothrombotic and thromboembolic events in atrial fibrillationIn adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with vitamin-K antagonists and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Secondary prevention of atherothrombotic eventsClopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Adult patients suffering from acute coronary syndrome: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). ST segment elevation acute myocardial infarction, in combination with ASA in patients undergoing percutaneous coronary intervention (including patients undergoing a stent placement) or medically treated patients eligible for thrombolytic/fibrinolytic therapy. In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS)Clopidogrel in combination with ASA is indicated in: Adult patients with moderate to high-risk TIA (ABCD2  score ≥4) or minor IS (NIHSS  ≤3) within 24 hours of either the TIA or IS event. Prevention of atherothrombotic and thromboembolic events in atrial fibrillationIn adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Secondary prevention of atherothrombotic events Clopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Adult patients suffering from acute coronary syndrome: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillationIn adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Secondary prevention of atherothrombotic eventsClopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Adult patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillationIn adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Prevention Secondary prevention of atherothrombotic events Clopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Adult patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillation: - In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Prevention of atherothrombotic events Clopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. For further information please refer to section 5. 1.
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: - Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. - Patients suffering from acute coronary syndrome: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

C16H16CLNO2S.H2SO4

419.9

419.026

C, 45.77; H, 4.32; Cl, 8.44; N, 3.34; O, 22.86; S, 15.27

120202-66-6

Clopidogrel;113665-84-2;Clopidogrel thiolactone;1147350-75-1;Clopidogrel-d3 hydrogen sulfate;1217643-68-9; 90055-48-4 (racemic); 120202-66-6 (sulfate);120202-67-7 (HBr); 120202-65-5 (HCl); 744256-69-7 (besylate);

115366

Off-white to light yellow solid powder

423.7ºC at 760 mmHg

184ºC

210ºC

3.965

140.76

2

8

4

26

463

1

COC(=O)[C@H](C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3.OS(=O)(=O)O

FDEODCTUSIWGLK-RSAXXLAASA-N

InChI=1S/C16H16ClNO2S.H2O4S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14;1-5(2,3)4/h2-5,7,9,15H,6,8,10H2,1H3;(H2,1,2,3,4)/t15-;/m0./s1

methyl (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate sulfate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.95 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.95 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 50 mg/mL (119.08 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。