Abstract
HSG4112, a racemic drug, is a new anti-obesity agent. In this study, the stereoselective pharmacokinetics of HSG4112 were investigated in rats and dogs, and the underlying mechanism was investigated. The plasma concentrations of HSG4112(S) and HSG4112(R) were quantitated in plasma from rats and beagle dogs after IV and/or oral administration of racemic HSG4112. The concentration of HSG4112(S) was significantly higher than that of HSG4112(R) in rat plasma. Contrarily, the concentration of HSG4112(R) was significantly higher than HSG4112(S) in dog plasma. A metabolic stability test with liver microsomes showed that HSG4112(S) was more stable than HSG4112(R) in rat liver microsomes, but the difference between stereoisomers did not appear in dog liver microsomes. However, the stereoselectivity was observed in dog liver and intestinal microsomes after uridine 5’-diphospho-glucuronic acid was added. Thus, stereoselective metabolism by uridine 5’-diphospho-glucuronosyltransferases is mainly responsible for the stereoselective pharmacokinetics in dogs. These results suggest that the species difference in the stereoselective plasma pharmacokinetics of HSG4112 is due to the stereoselective metabolism.
Highlights
HSG4112 is a new drug candidate which has been developed as a treatment for obesity
This stereoselective pharmacokinetic property in rats is supposedly due to the stereoselective metabolism of HSG4112
When HSG4112 was orally administered to beagle dogs, the concentration ratio (S/R) over time was 0.06–0.24, and the concentration of HSG4112(R) measured at a much higher level
Summary
HSG4112 is a new drug candidate which has been developed as a treatment for obesity. Its chemical structure is derived from glabridin. In spite of useful medicinal efficacy, glabridin is broken down by sunlight, moisture, acidity, basicity, oxygen, heat, and the like due to low chemical stability, so it is very difficult to develop a product utilizing glabridin [4]. For these reasons, we synthesized a new pyranochromenylphenol derivative, HSG4112, by modifying the structure of glabridin. QC samples were prepared at final concentrations of 5(LOQ), 15(low), 400(mid), and 4000(high) ng/mL in the same manner as the calibration standards
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