Abstract
Ticagrelor (AZD6140) is a reversibly binding oral P2Y12 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 h in 6 healthy male subjects receiving a single oral suspension dose of [14C]-ticagrelor 200 mg. Ticagrelor was rapidly absorbed with 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 h and 4.6 h, respectively). The ratio of radioactivity in plasma:whole blood was 1.69, suggesting 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. Inter-individual variability was small in both urine and fecal extracts with only small quantitative differences. All ten of the metabolites were fully or partially characterized and a full biotransformation pathway proposed for ticagrelor, in which oxidative loss of the hydroxyethyl sidechain from ticagrelor forms AR-C124910XX and a second oxidative pathway leads to N-dealkylation of ticagrelor forming AR-C133913XX.
Footnotes
- Received January 15, 2010.
- Accepted June 15, 2010.
- The American Society for Pharmacology and Experimental Therapeutics