Abstract: BACKGROUND AND AIM: To study toxicokinetics of CXY-001 in Beagle dogs, and evaluate the relationship between exposure response and dose. MATERIALS AND METHODS: Samples were analyzed with a validated LC-MS-MS method. In single dose study, the dosages of CXY-001 were 227, 511, 767, 1150 mg/kg . Blood samples were collected at 0.5, 1,2,3,4,5,6,8, 24 h after administration. In the 90-day repeated dose study, CXY-001 dosages were 120,30 and 7 mg/kg . On day 1, blood samples were collected at 0.5, 1,2,3,4,5,6,8, 24 h after administration. On day 45, blood samples were collected at 0.5,5,24 h and on day 90 at 30 min, 5,24,48,72 h. RESULTS: In single dose study, vomiting was observed. The CXY-001 AUC0-24 for doses 227,511,767,1 150 mg/kg were 150 249,263 905,232 640 and 19 848 ng•h/ml,respectively. The AUC0-∞ were 151 054, 298 069, 246 083 and 117 793 ng•h/ml,respectively. The Cmax were 13 400, 19 500, 29 100 and 6 910 ng•h/ml, respectively. In repeated dose study, the No-Observed-Adverse-Effect-Levle was 30 mg/kg. On day 1, the CXY-001 AUC0-24 for doses 120,30 and 7 mg/kg were (123 023±75 308),(19 246±14 654) and (2 991±996) ng•h/ml,respectively. AUC0-∞ were (200 189±106 688),(25 145±22 443) and (4 650±1 855) ng•h/ml,respectively. Cmax were (10 440± 5 891), (3 653±1 776) and (376±116) ng•h/ml, respectively. There was a slight difference of CXY-001 concentration at the same time point on day 45 and day 90,and CXY-001 concentration was below the low limit of quantitation at 48 h after last dose. CONCLUSION: Exposure response to CXY-001 generally increased with increasing dosage in Beagle dogs following oral dosing. These data suggest no accumulation was observed after stopping CXY-001 administration.

Key words: CXY-001, toxicokinetics, drug exposure