作者机构：
[李鑫] Hunan Provincial Key Lab of Diagnostic, Therapeutic Research in Chinese Medicine, Changsha, 410208, China;[蔡雄] Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China;[刘良] State Key Lab for Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macau
期刊：
Journal of Pharmaceutical and Biomedical Analysis,2020年177:112875 ISSN：0731-7085
通讯作者：
Liu, Rongxia;Wang, Wei
作者机构：
[Liu, Wanhui; Liu, Rongxia; Liu, Qianqian] Yantai Univ, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm, Minist Educ,Collaborat Innovat Ctr Adv Drug Deliv, Yantai 264005, Peoples R China.;[Cai, Xiong; Li, Bin; Wang, Wei; Liu, Leping] Hunan Univ Chinese Med, Sch Pharm, TCM & Ethnomed Innovat & Dev Int Lab, Innovat Mat Med Res Inst, Changsha 410208, Hunan, Peoples R China.;[Cheng, Dongsheng] Yantai Yuhuangding Hosp, Yantai 264000, Peoples R China.
通讯机构：
[Liu, Rongxia] Y;[Wang, Wei] H;Yantai Univ, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm, Minist Educ,Collaborat Innovat Ctr Adv Drug Deliv, Yantai 264005, Peoples R China.;Hunan Univ Chinese Med, Sch Pharm, TCM & Ethnomed Innovat & Dev Int Lab, Innovat Mat Med Res Inst, Changsha 410208, Hunan, Peoples R China.
关键词：
Excretion;Kadsura heteroclite;Metabolism;Pharmacokinetics;Schisanlactone E (SE);UHPLC-MS/MS & UHPLC-Q-Orbitrap HRMS
摘要：
Schisanlactone E (SE) is a bioactive ingredient extracted from the stem of Kadsura heteroclita (Roxb) Craib. SE has various pharmacological activity such as anti-tumor and anti-leukemia effects. However, its absorption, distribution, metabolism, and excretion have rarely been examined. In this study, new quali-quantitative analytical methods were developed for metabolic and pharmacokinetic studies of SE in rats. A UHPLC-MS/MS method was developed to determine SE in rat plasma, urine, and feces. Samples were precipitated with methanol and analyzed in multiple reaction monitoring mode. The established method was validated and applied to the pharmacokinetics, bioavailability, and excretion analysis of SE after oral (6mg/kg) or intravenous (2mg/kg) administration. The absolute oral bioavailability of SE was approximately 79.3%. After oral administration, SE was mainly excreted via feces with a rate of 41.7% for 48h. SE could not be detected in urine. Furthermore, a UHPLC-Q-Orbitrap HRMS method was developed for the metabolite screening of SE in rat plasma, urine, and feces. Metabolites were extracted by solid phase extraction and analyzed with full MS/dd-MS(2) scan mode. As a result, 15 metabolites including 11 phase I and 4 phase II metabolites were identified by a three-step analytical strategy. The carboxyl group, the five membered ring, and the six membered alpha,beta-unsaturated lactone ring of SE could be predicted as the main metabolic sites. This study provides comprehensive insights into the pharmacokinetic and metabolic profiles of SE, and would be valuable for future development and utilization of SE and Kadsura heteroclita.
作者机构：
[廖菁; 余黄合; 杨珍] Institute of Innovation and Applied Research in Chinese, Medicine Hunan University of Chinese Medicine, Changsha, 410208, China;[李鑫; 丁长松] Hunan Provincial Key Lab of Diagnostic and Therapeutic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China;[唐琳] School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China;[刘良] State Key Lab of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China;[林也; 张婷] Institute of Innovation and Applied Research in Chinese, Medicine Hunan University of Chinese Medicine, Changsha, 410208, China, Hunan Provincial Key Lab of Diagnostic and Therapeutic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
摘要：
ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases. AIM OF THE STUDY: The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models. MATERIALS AND METHODS: The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor (TNF-alpha) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot. RESULTS: The maximal tolerated single dose of KHS was determined to be 26g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100mg/kg and indomethacin at a dosage of 10mg/kg were used in both mice and rat models. CONCLUSION: These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1beta, IL-6, and TNF-alpha and inhibiting the proteins expression of COX-2 and iNOS.
作者：
SONG Hou-Pan;ZENG Mei-Yan;CHEN Xiao-Juan;CHEN Xin-Yi;YANG Yi-Jing;...
期刊：
数字中医药(英文),2019年2(3):136-146 ISSN：2096-479X
通讯作者：
Peng Jun
作者机构：
[CAI Xiong] Institute of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[ZENG Mei-Yan] College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[YANG Yi-Jing; ZHOU Ya-Sha; TIAN Ye; LIU Xiao-Qing] Hunan Provincial Key Laboratory for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine, Changsha, Hunan 410208, China;[PENG Jun] Department of Ophthalmology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China;[SONG Hou-Pan; CHEN Xiao-Juan; CHEN Xin-Yi] Institute of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China<&wdkj&>College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
通讯机构：
[Peng Jun] D;Department of Ophthalmology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
