Absorption, Distribution, Metabolism, and Excretion of Ticagrelor in Healthy Subjects

Abstract

Ticagrelor [(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino]-5-(propylthio)-a maximum plasma concentration at 1.5 h. The major active metabolite, AR-C124910XX, is formed by O-deethylation. Exposure to AR-C124910XX was 29% of peak and 40% of overall exposure to ticagrelor. In most subjects, radioactivity was undetectable in plasma after 20 h and whole blood after 12 h (half-life values of 6.3 and 4.6 h, respectively). The ratio of radioactivity in plasma to whole blood was 1.69, suggesting that ticagrelor and its metabolites are largely restricted to the plasma space. Mean radioactivity recovery was 26.5% in urine and 57.8% in feces. 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.

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

“…The most abundant drug-metabolizing enzyme in the liver is cytochrome P450 (CYP) 3A11,12, and clinically important interactions involving this enzyme are well documented12. Although ticagrelor is a direct-acting antiplatelet agent, it is metabolized to at least ten metabolites13. The major metabolite, AR-C124910XX, which is present at approximately 30–40% of the levels of ticagrelor13–17, is approximately equipotent in inhibiting platelet aggregation (AstraZeneca, data on file).…”

“…Given that the glucuronidated metabolite is highly polar and expected to be excreted rapidly in the urine, and the hydroxylated metabolite is minor, the pharmacological relevance of these biotransformations is likely to be minimal13.…”

Does morphine administration affect ticagrelor conversion to its active metabolite in patients with acute myocardial infarction? A sub-analysis of the randomized, double-blind, placebo- -controlled IMPRESSION trial

“…In addition, ticagrelor is extensively metabolized to about ten compounds. Ticagrelor main active metabolite, AR-C124910XX, which is formed by ticagrelor O-de-ethylation through cytochrome P450 CYP3A4 and CYP3A43A5 enzymes, has a similar P2Y12 receptor potency as the parent drug and seems to exert antiplatelet action comparable to ticagrelor [7,8]. The concentration of AR-C124910XX is reported to be approximately one third of the parent drug [7][8][9].…”

“…A predictable and linear pharmacokinetics of ticagrelor and AR-C124910XX have been demonstrated in a wide spectrum of patients, including those with stable coronary artery disease and acute coronary syndromes [10,11]. Both, circulating ticagrelor and its active metabolite, undergo N-dealkylation and/or glucuronidation, and are finally eliminated via feces and urine in an inactive state [8].…”

“…Ticagrelor main active metabolite, AR-C124910XX, which is formed by ticagrelor O-de-ethylation through cytochrome P450 CYP3A4 and CYP3A43A5 enzymes, has a similar P2Y12 receptor potency as the parent drug and seems to exert antiplatelet action comparable to ticagrelor [7,8]. The concentration of AR-C124910XX is reported to be approximately one third of the parent drug [7][8][9]. A predictable and linear pharmacokinetics of ticagrelor and AR-C124910XX have been demonstrated in a wide spectrum of patients, including those with stable coronary artery disease and acute coronary syndromes [10,11].…”