Comparative pharmacokinetic studies of andrographolide and its metabolite of 14-deoxy-12-hydroxy-andrographolide in rat by ultra-performance liquid chromatography-mass spectrometry

摘要

Andrographolide (AND), one of the major diterpenoids from Andrographis paniculata (Burm. f.) Nees, can be metabolized as a phase two metabolite of 14-deoxy-12-hydroxy-andrographolide-19-O-β-d-glucuronide in human. The aim of this study is to characterize and synthesize the phase one metabolite of 14-deoxy-12-hydroxy-andrographolide (DEO-AND) after gavage feeding of AND in rats, and to compare the pharmacokinetics of AND and DEO-AND after intravenous administration. DEO-AND was first discovered existing in rat serum by HPLC-MSn after administration of AND. Furthermore, the target metabolite was synthesized and elucidated by NMR. In addition, a rapid, selective and sensitive UPLC-ESI/MS method was developed for the first time to determine the content of AND and DEO-AND in rats serum. The method was successfully applied to a pharmacokinetic study in rats after a single intravenous dose of 5 mg/kg AND and DEO-AND, respectively. In comparison, the pharmacokinetic parameters of metabolite DEO-AND, including distribution rate constant, elimination rate constant, half-life and mean residence time, were significantly less than those of AND (p0.05). However, the AUC0→720 min value after intravenous administration of DEO-AND was 781.59±81.46 μg min/mL, which was 17.71 times higher than that of AND (44.13±10.45 μg min/mL; p0.05). These results show the pharmacokinetic profile of AND to be significantly different from that of DEO-AND by intravenous administration.