Disposition and Metabolism of Ticagrelor, a Novel P2Y12 Receptor Antagonist, in Mice, Rats, and Marmosets

Abstract

Ticagrelor is a reversibly binding and selective oral P2Y(12) antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [(14)C]ticagrelor was investigated in mice, rats, and marmosets to demonstrate that these preclinical toxicity species showed similar metabolic profiles to human. Incubations with hepatocytes or microsomes from multiple species were also studied to compare with in vivo metabolic profiles. The routes of excretion were similar for both oral and intravenous administration in mice, rats, and marmosets with fecal excretion being the major elimination pathway accounting for 59 to 96% of the total radioactivity administered. Urinary excretion of drug-related material accounted for only 1 to 15% of the total radioactivity administered. Milk samples from lactating rats displayed significantly higher levels of total radioactivity than plasma after oral administration of ticagrelor. This demonstrated that ticagrelor and/or its metabolites were readily transferred into rat milk and that neonatal rats could be exposed to ticagrelor-related compounds via maternal milk. Ticagrelor and active metabolite AR-C124910 (loss of hydroxyethyl side chain) were the major components in plasma from all species studied and similar to human plasma profiles. The primary metabolite of ticagrelor excreted in urine across all species was an inactive metabolite, AR-C133913 (loss of difluorophenylcyclopropyl group). Ticagrelor, AR-C124910, and AR-C133913 were the major components found in feces from the three species examined. Overall, in vivo metabolite profiles were qualitatively similar across all species and consistent with in vitro results.