Disposition and metabolism of ticagrelor, a novel P2Y 12 receptor antagonist, in mice, rats, and marmosets

Drug Metabolism and Disposition

Volumn 39, Issue 9, 2011, Pages 1555-1567

  Li, Yan ^a   Landqvist, Claire ^b   Grimm, Scott W ^a  

^a ASTRAZENECA   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

AR C 124910; AR C 133913; DRUG METABOLITE; TICAGRELOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CALLITRICHINAE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DISPOSITION; DRUG ELIMINATION; DRUG EXCRETION; DRUG METABOLISM; DRUG MILK LEVEL; FEMALE; HUMAN; HUMAN CELL; IN VIVO STUDY; LIVER CELL; LIVER MICROSOME; MALE; MOUSE; NEWBORN; NONHUMAN; PRIORITY JOURNAL; RAT; SINGLE DRUG DOSE; SPECIES COMPARISON; URINARY EXCRETION;

ADENOSINE; ADMINISTRATION, ORAL; ANIMALS; CALLITHRIX; DOGS; FECES; FEMALE; HEPATOCYTES; HUMANS; INJECTIONS, INTRAVENOUS; MALE; METABOLIC DETOXICATION, DRUG; MICE; MICROSOMES, LIVER; MILK; PURINERGIC P2Y RECEPTOR ANTAGONISTS; RATS; RATS, SPRAGUE-DAWLEY;

MUS; RATTUS;

EID: 80051964777     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.111.039669     Document Type: Article

References (22)

1. Amar-Costesec A., Beaufay H., Wibo M., Thinès-Sempoux D., Feytmans E., Robbi M, and Berthet J. (1974) Analytical study of microsomes and isolated subcellular membranes from rat liver. II. Preparation and composition of the microsomal fraction. J Cell Biol 61:201-212.
2. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, et al. (2007) Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 28:1598-1660.
3. Butler K and Teng R. (2010) Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 70:65-77.
4. Cannon C.P., Husted S., Harrington R.A., Scirica B.M., Emanuelsson H., Peters G., Storey RF, and DISPERSE-2 Investigators (2007) Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST- STSegment elevation acute coronary syndrome: primary results of the DISPERSE- STSegment elevation acute coronary syndrome: primary results of the DISPERSE2 trial. J Am Coll Cardiol 50:1844-1851. (Pubitemid 350007959)
5. Davies M.J., Thomas A.C., Knapman PA, and Hangartner J.R. (1986) Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 73:418-427. (Pubitemid 16133019)
6. Farid N.A., Kurihara A, and Wrighton S.A. (2010) Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 50:126-142.
7. Fitzgerald D.J., Roy L., Catella F, and FitzGerald G.A. (1986) Platelet activation in unstable coronary disease. N Engl J Med 315:983-989. (Pubitemid 16028578)
8. Gershlick A.H. (2000) Antiplatelet therapy. Hosp Med 61:15-23.
9. 12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27:1038-1047.
10. Ito S and Lee A. (2003) Drug excretion into breast milk- Overview. Adv Drug Deliv Rev 55:617-627. (Pubitemid 36428675)
11. Jonker J.W., Merino G., Musters S., Van Herwaarden A.E., Bolscher E., Wagenaar E., Mesman E., Dale TC, and Schinkel A.H. (2005) The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 11:127-129. (Pubitemid 40321346)
12. Roffey S.J., Obach R.S., Gedge JI, and Smith D.A. (2007) What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabelled drugs. Drug Metab Dispos 37:74-81.
13. Schrör K. (1995) Antiplatelet drugs. A comparative review. Drugs 50:7-28.
14. Seglen P.O. (1976) Preparation of isolated rat liver cells. Methods Cell Biol 13:29-83.
15. Sillén H., Cook M, and Davis P. (2010) Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:2299-2306.
16. Springthorpe B., Bailey A., Barton P., Birkinshaw T.N., Bonnert R.V., Brown R.C., Chapman D., Dixon J., Guile S.D., Humphries R.G., et al. (2007) From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 17:6013-6018. (Pubitemid 47446193)
17. Tantry U.S., Bliden KP, and Gurbel P.A. (2007) AZD6140. Expert Opin Investig Drugs 16:225-229. (Pubitemid 46206636)
18. 12 receptor antagonist, has linear pharmacokinetics and provides near complete inhibition of platelet aggregation, with reversibility of effect, in healthy subjects. Can J Clin Pharmacol 15:e426.
19. Teng R., Oliver S., Hayes MA, and Butler K. (2010) Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 38:1514-1521.
20. Van Herwaarden AE and Schinkel A.H. (2006) The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol Sci 27:10-16. (Pubitemid 43063119)
21. Yusuf S., Zhao F., Mehta S.R., Chrolavicius S., Tognoni G., Fox KK, and Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST- Segment elevation. N Engl J Med 345:494-502. (Pubitemid 32758501)
22. Zhou D., Andersson TB, and Grimm S.W. (2011) In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics. Drug Metab Dispos 39:703-710.