Stereoselective pharmacokinetic properties of HY001, a new drug candidate

Abstract

ABSTRACT

HY001, a new drug candidate was developed as a treatment for obesity and diabetes mellitus. The structure of HY001 has a chiral center. The aim of this study was to quantify HY001(S) and HY001(R) in plasma samples obtained after administration of HY001 in 4 different species (rat, mouse, beagle dog and monkey) and to compare the metabolic stability of HY001(S) and HY001(R) in liver and intestinal microsomes from five different species (rat, mouse, dog, monkey and human) using LC-MS/MS analysis. Concentration ratios of HY001(S) and HY001(R) in rat and dog plasma were significantly different. Concentration of HY001(S) in rat plasma sample was significantly higher than that of HY001(R). Concentration of HY001(R) in beagle dog plasma sample was significantly higher than HY001(S). Metabolic stability test showed that the metabolic stability of HY001(S) in rat liver microsome was higher than that of HY001(R). Metabolic stability test showed that metabolic stability of HY001(R) was higher than that of HY001(S) after addition of UDPGA to dog liver and intestinal microsome. These results suggest that the difference in metabolic stability between HY001(S) and HY001(R) in rat is thought to be due to stereoselective metabolism by liver microsome and the difference in metabolic stability between HY001(S) and HY001(R) in beagle dog is thought to be due to stereoselective metabolism by glucuronidation, a type of phase 2 metabolism by liver and intestinal microsome.