A t-test was then performed on these log-transformed AUC values. Statistical analysis was not performed on the data SB431542 concentration at each individual time point. The two year rat carcinogenicity bioassay evaluated Ticagrelor at 0, 20, 60 and 180/120 mg/kg/day with female high dose being 180

and male high dose being 120 mg/kg/day. The AUC exposure of Ticagrelor in high dose female rats (Table 1) remained relatively consistent between Day 1, Week 26 and Week 52, whereas exposure of the metabolite increased between Day 1 and Week 26 and then was similar between Week 26 and Week 52. At 60 mg/kg/day male rats had lower Ticagrelor exposure and higher metabolite exposure, compared to female rats. Microscopic examination of the tissues revealed that the high dose treated female rats (180 mg/kg/day) had a statistically significantly

increased incidence selleck chemical of uterine adenocarcinomas (p < 0.001), while there were statistically significantly decreased incidences of tumors/hyperplasia in the pituitary (p < 0.05), and mammary (p < 0.05) glands (Table 2). The treatment related effect in the high dose rats (180 mg/kg/day) on the incidence of mammary tumors (decreased) and uterine tumors (increased) are shown in Figure 2. The coincidence between mammary and uterine tumors showed an inverse relationship in that the rats with a uterine tumor did not have mammary tumors and the rats with mammary tumors

did not have a uterine tumor. Verteporfin Male and female rats in the control and Ticagrelor groups gained body weight throughout the study but the male Ticagrelor-treated rats gained less body weight than the controls over the study period in a dose trend, with the high dose group weighing within 10% of the control group at the end of the study. The body weights of the Ticagrelor low and mid dose treated female rats were similar to the control group (data not shown), but the body weights of the high dose treated (180 mg/kg/day) female rats were significantly less (p < 0.001) than the control rats, starting at approximately Week 50 through to the end of study and were approximately 20% lower than the control group by the end of study (Figure 3a). There were no consistent food consumption differences with Ticagrelor treatment in male rats but in female rats treated with high dose Ticagrelor (180 mg/kg/day) there was increased food consumption early during the study and then significantly decreased food consumption in 10 out of the last 14 measurements (Figure 3b; p < 0.05), such that the decreased food intake starting at Week 52 (food intake measured every 4 weeks after Week 28) corresponded with the decreased body weight gain starting at Week 50. The Ames, mouse lymphoma and micronucleus assays for ticagrelor, and Ames and mouse lymphoma assays for major metabolites were negative (Table 3).