Metabolic characterization of a potent natural neuroprotective agent dendrobine in vitro and in rats  

作　　者：Hong Pan Fu-guo Shi Chao Fang Jing-shan Shi 

机构地区：[1]Hongqiao International Institute of Medicine,Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacology and Chemical Biology,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China [2]Key Laboratory of Basic Pharmacology of Ministry of Education&Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi,563003,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期1059-1071,共13页中国药理学报（英文版）

基　　金：This study was financially supported by the National Natural Science Foundation of China[U1812403];the Pharmacy National First-class Discipline Construction Project of Guizhou Province of China[GNYL(2017-006)].

摘　　要：Dendrobine is the main sesquiterpene alkaloid of Dendrobium nobile Lindl, which exhibits potent neuroprotective activity. However, its metabolism and disposition are little known. In this study, we investigated the metabolic characteristics of dendrobine in vitro and in rats. The metabolic stability and temporal profile of metabolites formation of dendrobine were assayed in human/rat liver microsomal and S9 fractions. Dendrobine metabolites were separated and identified mainly by UPLC-Q/Orbitrap MS. After oral administration of dendrobine (50 mg/kg) to rats, the accumulative excretion rate of dendrobine in feces, urine, and bile was 0.27%, 0.52%, and 0.031%, respectively, and low systematic exposure of dendrobine (AUC0–∞ = 629.2 ± 56.4 ng·h/mL) was observed. We demonstrated that the elimination of dendrobine was very rapid in liver microsomal incubation (the in vitro elimination t1/2 in rat and human liver microsomes was 1.35 and 5.61 min, respectively). Dendrobine underwent rapid and extensive metabolism;cytochrome P450, especially CYP3A4, CYP2B6, and CYP2C19, were mainly responsible for its metabolism. Aldehyde dehydrogenase, alcohol dehydrogenase and aldehyde oxidase were involved in the formation of carboxylic acid metabolites. By the aid of in-source fragmentation screening, hydrogen/deuterium exchange experiment, post-acquisition processing software, and available reference standards, 50 metabolites were identified and characterized in liver microsomal incubation and in rats. The major metabolic pathways of dendrobine were N-demethylation, N-oxidation, and dehydrogenation, followed by hydroxylation and glucuronidation. Collectively, the metabolic fate of dendrobine elucidated in this study not only yields benefits for its subsequent metabolism study but also facilitates to better understanding the mode of action of dendrobine and evaluating the pharmacologic efficiency of the high exposure metabolites.

关 键 词：DENDROBINE neuroprotective agent drug metabolism cytochrome P450 metabolic stability UPLC-Q/Orbitrap MS 

分 类 号：R965[医药卫生—药理学]