Ticagrelor (AZD6140)   中文名称: 替卡格雷

与其他 P2Y12R 拮抗剂相比，替格瑞洛可更好地抑制缺血性血小板中 5'-二磷酸腺苷 (ADP) 诱导的 Ca2+ 释放。除了对 P2Y12R 的拮抗作用外，替格瑞洛还抑制血小板上的平衡核苷转运蛋白 1 (ENT1)，从而导致细胞外腺苷积累和 Gs 偶联腺苷 A2A 受体被激活[1]。与用盐水治疗的小鼠相比，B16-F10 细胞与用替格瑞洛治疗的小鼠的血小板的相互作用较少[2]。

在 B16-F10 黑色素瘤静脉内和脾内转移模型中，给予治疗剂量的替格瑞洛（10 mg/kg）的小鼠显示肺（84%）和肝（86%）转移显着减少。此外，用替格瑞洛治疗的动物比用盐水治疗的动物有更高的存活率。在 4T1 乳腺癌模型中也看到了类似的结果，其中替格瑞洛治疗减少了肺 (55%) 和骨髓 (87%) 转移[2]。口服替卡格雷（1-10 mg/kg）一次对血小板聚集具有剂量相关的抑制作用。当替格瑞洛最大剂量为10 mg/kg时，血小板聚集在用药后一小时开始受到显着抑制，并在四小时后达到峰值[3]。

Absorption, Distribution and Excretion
Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a Cmax of 923ng/mL, with a Tmax of 1.5 hours and an AUC of 6675ng\*h/mL. The active metabolite of ticagrelor reaches a Cmax of 264ng/mL, with a Tmax of 3.0 hours and an AUC of 2538ng\*h/mL.
A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine.
The steady state volume of distribution of ticagrelor is 88 L.
The renal clearance of ticagrelor is 0.00584L/h.
The drug is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to an active metabolite that has similar antiplatelet activity as the parent drug.Plasma concentrations of ticagrelor and its active metabolite increase in a dose-dependent manner with peak concentrations achieved within approximately 1.5 and 2.5 hours, respectively. Ticagrelor is primarily eliminated in the feces and to a lesser extent in urine; less than 1% of a dose is recovered in urine as the parent drug and active metabolite. ... Both ticagrelor and its active metabolite are extensively (more than 99%) bound to human plasma proteins. Administration with a high-fat meal increases systemic exposure of ticagrelor by 21% and decreases peak plasma concentrations of the active metabolite by 22%, but has no effect on peak plasma concentrations of ticagrelor or on systemic exposure to the active metabolite.
Ticagrelor is rapidly absorbed following oral administration.
The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion.
/MILK/ It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk.
For more Absorption, Distribution and Excretion (Complete) data for Ticagrelor (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated.
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
The drug is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to an active metabolite that has similar antiplatelet activity as the parent drug.
Ticagrelor is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. The pharmacokinetics, metabolism, and excretion of ticagrelor were investigated over 168 hr in six healthy male subjects receiving a single oral suspension dose of 200 mg of (14)C-ticagrelor. ... Major circulating components in the plasma and feces were identified as ticagrelor and AR-C124910XX, whereas in urine the major components were metabolite M5 (AR-C133913XX) and its glucuronide conjugate M4. Levels of unchanged ticagrelor and AR-C124910XX were <0.05% in the urine, indicating that renal clearance of ticagrelor and AR-C124910XX is of minor importance. Interindividual variability was small in both urine and fecal extracts with only small quantitative differences. All 10 of the metabolites were fully or partially characterized and a full biotransformation pathway was proposed for ticagrelor, in which oxidative loss of the hydroxyethyl side chain from ticagrelor forms AR-C124910XX and a second oxidative pathway leads to N-dealkylation of ticagrelor, forming AR-C133913XX.

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Biological Half-Life
Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours.
The mean terminal half-lives of ticagrelor and its active metabolite reportedly are about 7 and 9 hours, respectively.
Ticagrelor is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. The pharmacokinetics, metabolism, and excretion of ticagrelor were investigated over 168 hr in six healthy male subjects receiving a single oral suspension dose of 200 mg of (14)C-ticagrelor. In most subjects, radioactivity was undetectable in plasma after 20 hr and whole blood after 12 hr (half-life values of 6.3 and 4.6 hr, respectively).

Toxicity Summary
IDENTIFICATION AND USE: Ticagrelor is a crystalline powder. As the drug Brilinta, it is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). Brilinta also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose may include bleeding, gastrointestinal effects (nausea, vomiting and diarrhea) and ventricular pauses. Blood loss is the predominant risk. ANIMAL STUDIES: The acute toxicity of the drug is considered low. The results of single dose studies in mice and rats showed that ticagrelor was well tolerated when given orally by gavage at doses approximately 550 times the recommended human daily dose on a mg/kg basis. Repeat-dose studies were conducted in mice, rats and marmosets. Indications of subclinical bleeding were observed across species. Increased liver weight at high doses occurred in rodents. Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the human therapeutic exposure), but did cause maternal and developmental toxicity in pups at 180 mg/kg. Ticagrelor given during the period of organogenesis had no effect on fetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the human therapeutic exposure). Ticagrelor and the active metabolite AR-C124910XX did not demonstrate any genotoxic potential in bacterial in vitro test, in vitro mouse lymphoma L5178Y TK+/- 3.7.2C cell, and in vivo rat bone marrow micronucleus assays.

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Hepatotoxicity
In several large clinical trials, ticagrelor was not associated with serum enzyme elevations during therapy and no instances of clinically apparent liver injury were reported. While there have been isolated reports of transient and mild serum enzyme elevations during ticagrelor therapy, these have been short lived and asymptomatic. In addition, since marketing and release, there have been no reports of isolated clinically apparent liver injury or jaundice associated with ticagrelor therapy and hepatotoxicity is not mentioned in the product label. On the other hand, there have been several reports of jaundice and liver injury associated with rhabdomyolysis and with thrombotic thrombocytopenic purpura that represented secondary effects of these severe adverse events. Thus, significant liver injury due to ticagrelor occurs but has occurred largely in association with other life-threatening complications.
Likelihood score: D (possible rare cause of liver injury due to complications of severe allergic reactions or drug-drug interactions).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of ticagrelor during breastfeeding. Because ticagrelor and its active metabolite are more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, 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.

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Protein Binding
Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin.

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Interactions
Concomitant administration of ticagrelor and digoxin did not substantially affect pharmacokinetics of digoxin; therefore, these drugs may be used concomitantly without dosage adjustments. However, because of the possibility of increased digoxin concentrations as a result of P-glycoprotein inhibition, serum digoxin concentrations should be monitored during initiation of and following any change in ticagrelor therapy.
When ticagrelor is used in conjunction with aspirin maintenance dosages exceeding 100 mg daily, efficacy of ticagrelor may be reduced.
Ticagrelor is a substrate and weak inhibitor of the P-glycoprotein transport system. Increased serum concentrations of P-glycoprotein substrates (e.g., digoxin) are possible when these drugs are used concomitantly with ticagrelor; appropriate laboratory and/or clinical monitoring is recommended.
Concomitant administration of ticagrelor and rifampin 600 mg once daily substantially decreased peak plasma concentrations of and systemic exposure to ticagrelor. Concomitant use of ticagrelor and rifampin should therefore be avoided.
For more Interactions (Complete) data for Ticagrelor (9 total), please visit the HSDB record page.

[1]. Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor. Blood. 2016 Dec 8;128(23):2717-2728.

[2]. The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int J Cancer. 2015 Jan 1;136(1):234-40.

[3]. A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats. Br J Pharmacol. 2013 May;169(1):82-9.

Therapeutic Uses
Purinergic P2Y Receptor Antagonists
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Ticagrelor is included in the database.
Brilinta is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). For at least the first 12 months following ACS, it is superior to clopidogrel. /Included in US product label/
Brilinta also reduces the rate of stent thrombosis in patients who have been stented for treatment of acute coronary syndrome (ACS). /Included in US product label/

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Drug Warnings
/BOXED WARNING/ BLEEDING RISK. Brilinta, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. Do not use Brilinta in patients with active pathological bleeding or a history of intracranial hemorrhage. Do not start Brilinta in patients undergoing urgent coronary artery bypass graft surgery (CABG). If possible, manage bleeding without discontinuing Brilinta. Stopping Brilinta increases the risk of subsequent cardiovascular events
/BOXED WARNING/ ASPIRIN DOSE AND BRILINTA EFFECTIVENESS. Maintenance doses of aspirin above 100 mg reduce the effectiveness of Brilinta and should be avoided.
In general, treatment with ticagrelor should not be discontinued prematurely because this increases the risk of cardiovascular events. Premature discontinuance of antiplatelet therapy (e.g., P2Y12 adenosine diphosphate (ADP)-receptor antagonists, aspirin) in patients with coronary artery stents has been associated with an increased risk of ischemic cardiovascular events (e.g., stent thrombosis, myocardial infarction (MI), death). If temporary discontinuance of ticagrelor is necessary such as prior to elective surgery or for management of bleeding, the drug should be restarted as soon as possible. Patients should be advised to never stop taking ticagrelor without first consulting the prescribing clinician, even if instructed by another clinician (e.g., dentist) to stop such therapy. Prior to scheduling an invasive procedure, patients should inform clinicians (including dentists) that they are currently taking ticagrelor and clinicians performing the invasive procedure should consult with the prescribing clinician before discontinuing such therapy.
Bradyarrhythmias, including ventricular pauses, have occurred in patients receiving ticagrelor. In the The Study of Platelet Inhibition and Patient Outcomes (PLATO) study, Holter monitor-detected ventricular pauses of at least 3 seconds were reported more frequently during the first week of therapy in patients receiving ticagrelor than in those receiving clopidogrel (5.8 versus 3.6%, respectively). There was no difference in the overall risk of clinically important bradycardic effects (e.g., syncope, need for pacemaker insertion) between the treatment groups. Ventricular pauses were mostly asymptomatic and attributed to sinoatrial nodal suppression. Patients with a baseline increased risk of bradycardia (e.g., those with sick sinus syndrome, second- or third-degree AV block, syncope due to bradycardia without a pacemaker) were excluded from the PLATO study; therefore, some clinicians recommend that ticagrelor be used with caution in such patients.
For more Drug Warnings (Complete) data for Ticagrelor (15 total), please visit the HSDB record page.

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Pharmacodynamics
Ticagrelor is a P2Y₁₂ receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias.

C23H28F2N6O4S

522.57

522.186

274693-27-5

9871419

Off-white to yellow solid powder

1.7±0.1 g/cm3

777.6±70.0 °C at 760 mmHg

424.0±35.7 °C

0.0±2.8 mmHg at 25°C

1.744

1.9

163.74

4

12

10

36

736

6

CCCSC1=NC(=C2C(=N1)N(N=N2)[C@@H]3C[C@@H]([C@H]([C@H]3O)O)OCCO)N[C@@H]4C[C@H]4C5=CC(=C(C=C5)F)F

OEKWJQXRCDYSHL-FNOIDJSQSA-N

InChI=1S/C23H28F2N6O4S/c1-2-7-36-23-27-21(26-15-9-12(15)11-3-4-13(24)14(25)8-11)18-22(28-23)31(30-29-18)16-10-17(35-6-5-32)20(34)19(16)33/h3-4,8,12,15-17,19-20,32-34H,2,5-7,9-10H2,1H3,(H,26,27,28)/t12-,15+,16+,17-,19-,20+/m0/s1

(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

AZD 6140; AZD 6140; AR-C 126532XX; AR-C-126532XX; AZD-6140; AZD6140; AR-C126532XX; Ticagrelor; brand name: Brilinta; Brilique; Possia

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： (1). 本产品在运输和储存过程中需避光。  (2). 请将本产品存放在密封且受保护的环境中（例如氮气保护），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 mg/mL (3.83 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 20.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2 mg/mL (3.83 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 20.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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 3 中的溶解度: ≥ 2 mg/mL (3.83 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 20.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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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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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。