Pharmacokinetics and Bioavailability of New Synthetic 5-HT2C Agonists, KKHQ80109 and KKHQ80114, in Sprague-Dawley Rats

Abstract

5-HT2C receptors have been considered as therapeutic targets for the treatment of various central nervous system disorders such as depression, anxiety, epilepsy, schizophrenia, and sleep disorders. We chemically synthesized KKHQ80109 (K09) and KKHQ80114 (K14), selective 5-HT2C agonists, with the purpose of developing therapeutic agents for the treatment of obesity. The objective of this work is to investigate pharmacokinetic parameters and bioavailability of K09 and K14 in rats given orally or intravenously. Oral administration of 20 mg/kg K09 results in 4.11 hr of the terminal half-life and 89.16 ng/ml of Cmax at 5.00 hr (Tmax). The terminal half-life of K14 was 3.83 hr with 215.81 ng/ml of Cmax at 3.33 hr (Tmax) after oral dosing of 20 mg/kg K14, indicating that K14 is more rapidly absorbed than K09. Bioavailability showed 0.17-0.21 for K09 and 0.19-0.23 for K14. Urinary excretion of parent K09 and K14 was less than 1%, indicating that K09 and K14 undergo very extensive hepatic metabolism.