生物活性

• 描述P2Y(12) plays an important role in regulating platelet aggregation and function. This receptor is the primary target of thienopyridine antiplatelet agents, the active metabolites of which bind irreversibly to the receptor, and of newer agents that can directly and reversibly modulate receptor activity^[7]. Ticagrelor (AZD6140) is a reversible oral P2Y12 receptor antagonist for the treatment of platelet aggregation, with a K_i value of 2 nM^[7]. Ticagrelor moderately inhibited CYP2C9 activity in human liver microbodies, while it had almost no inhibitory activity for CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1. In human liver microsomes, ticagrelor inhibited 4-hydroxylation of midazolam and activated 1-hydroxylation of midazolam. It was assessed in fresh human hepatocytes that ticagrelor was not an inducer of CYP1A2 or CYP3A4^[8]. B16-F10 cells exhibited decreased interaction with platelets from ticagrelor-treated mice compared to saline-treated mice^[9]. In B16-F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline-treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment^[9]. Single oral administration of ticagrelor (1-10 mg/kg) caused dose-related inhibitory effect on platelet aggregation. Ticagrelor, at the highest dose (10 mg/kg) significantly inhibited platelet aggregation at 1h after dosing and the peak inhibition was observed at 4h after dosing^[10].

• 动物研究
  剂量	Rat: 10 mg/kg - 30 mg/kg[3] (i.p.); 1 mg/kg - 30 mg/kg[4] (p.o.) Mice: 3 mg/kg[5] (p.o.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Rats[6] Dose 10 mg/kg Administration p.o. AUC0→24h 1431.30 ng·h/ml T1/2 2.94 h Tmax 1.40 h Cmax 296.53 ng/ml AUC0→∞ 1479.91 ng·h/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02482298	-	-	Completed	-	-
  NCT02482298	Sickle Cell Disease	Phase 2	Completed	-	United States, Florida ... more >> Research Site Miami, Florida, United States, 33136 United States, Maryland Research Site Bethesda, Maryland, United States, 20817 United States, South Carolina Research Site Charleston, South Carolina, United States, 29425 Egypt Research Site Alexandria, Egypt, 21131 Research Site Cairo, Egypt, 11566 Research Site Cairo, Egypt France Research Site Bordeaux Cedex, France, 33076 Research Site Strasbourg, France, 67091 Italy Research Site Verona, Italy, 37134 Kenya Research Site Kisian, Kenya, 40100 Research Site Kisumu, Kenya, 40100 Research Site Nairobi, Kenya, 00100 Lebanon Research Site Beirut, Lebanon, 1107 2020 Research Site Beirut, Lebanon, 113-6044 Turkey Research Site Adana, Turkey, 01130 Research Site Mersin, Turkey, 33079 Research Site Van, Turkey, 65080 United Kingdom Research Site Harrow, United Kingdom, HA1 3UJ Research Site London, United Kingdom, E1 1BB Research Site London, United Kingdom, E9 6SR Collapse <<
  NCT03129867	-	-	Not yet recruiting	December 31, 2019	-

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• 参考文献

• [1] Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010 May;66(5):487-96.

  [2] VAN Giezen JJ, Nilsson L, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009 Sep;7(9):1556-65.

  [3] Ye Y, Birnbaum GD, et al. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1805-14.

  [4] Sugidachi A, Ohno K, et al. 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.

  [5] Lancellotti P, Musumeci L, et al. Antibacterial Activity of Ticagrelor in Conventional Antiplatelet Dosages Against Antibiotic-Resistant Gram-Positive Bacteria. JAMA Cardiol. 2019 Jun 1;4(6):596-599.

  [6] Na YG, Byeon JJ, et al. Pharmacokinetic/Pharmacodynamic Modeling To Predict the Antiplatelet Effect of the Ticagrelor-Loaded Self-Microemulsifying Drug Delivery System in Rats. Mol Pharm. 2020 Feb 24.

  [7] VAN Giezen JJ, Nilsson L, Berntsson P, Wissing BM, Giordanetto F, Tomlinson W, Greasley PJ. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009 Sep;7(9):1556-65. doi: 10.1111/j.1538-7836.2009.03527.x. Epub 2009 Jun 23. PMID: 19552634.

  [8] Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics. Drug Metab Dispos. 2011 Apr;39(4):703-10. doi: 10.1124/dmd.110.037143. Epub 2010 Dec 22. PMID: 21177984.

  [9] Gebremeskel S, LeVatte T, Liwski RS, Johnston B, Bezuhly M. 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. doi: 10.1002/ijc.28947. Epub 2014 May 14. PMID: 24798403.

  [10] Sugidachi A, Ohno K, Ogawa T, Jakubowski J, Hashimoto M, Tomizawa A. 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. doi: 10.1111/bph.12108. PMID: 23347039; PMCID: PMC3632240.

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