盐酸二甲双胍、食物和乙醇对桑枝总生物碱药代动力学的影响  

Pharmacokinetic effects of metformin hydrochloride,food and alcohol on Ramulus Mori(Sangzhi)alkaloids

作　　者：赵吭 冯遇 纪文明 王丽 刘志华 于敬涵 程佳玲 叶军[1,2,3] 夏学军 刘玉玲[1,2,3] ZHAO Hang;FENG Yu;JI Wen-ming;WANG Li;LIU Zhi-hua;YU Jing-han;CHENG Jia-ling;YE Jun;XIA Xue-jun;LIU Yu-ling(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing I00050,China;Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Wehand-Bio Pharmaceutical Co.,Ltd.,Bejjing 102600,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,北京100050 [2]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [3]中国医学科学院、北京协和医学院药物研究所,药物传输技术及新型制剂北京市重点实验室,北京100050 [4]北京五和博澳药业有限公司,北京102600

出　　处：《药学学报》2023年第12期3674-3683,共10页Acta Pharmaceutica Sinica

基　　金：中国医学科学院创新工程项目(2022-I2M-2-002)

摘　　要：桑枝总生物碱(SZ-A)是来源于桑枝的多羟基生物碱有效组分,用于治疗2型糖尿病(T2DM),口服后除在小肠发挥糖苷酶抑制剂作用外,还可吸收入血,广泛分布于糖尿病相关靶器官,发挥多重药理作用。阐明SZ-A可能存在的药代动力学影响因素,如药物相互作用、食物及乙醇对SZ-A吸收的影响等,对其临床合理用药十分重要,然而这方面的研究却十分有限。因此,本研究首先进行了SD大鼠灌胃给药SZ-A(50mg·kg^(-1))与盐酸二甲双胍(200mg·kg^(-1))之间的药代动力学相互作用研究。然后,以大鼠空腹给药SZ-A(50mg.kg^(-1))为对照,研究了食物(标准饲料)对SZ-A药代动力学的影响。最后,以大鼠给药SZ-A(50mg·kg^(-1))水溶液为对照,考察了SZ-A不同浓度的乙醇溶液的药代动力学特征,评价乙醇对SZ-A生物吸收的影响。结果表明,SZ-A与盐酸二甲双胍联合给药后没有产生明显的药代动力学相互作用。标准食物对SZ-A的药代特征几乎没有影响。乙醇延缓了SZ-A的吸收,使SZ-A的C_(max)显著降低,且乙醇浓度越高降低程度越大,但是AUC_(0-t)没有显著性差异。本研究结果为SZ-A的临床合理用药提供了更多数据支持。所有动物实验方案均经康泰医学检验服务河北有限公司(中国河北)伦理委员会批准(批准号:MDL2022-01-17-1)。Ramulus Mori(Sangzhi)alkaloids(SZ-A)are a group of polyhydroxy alkaloids extracted and isolated from the traditional Chinese medicine mulberry twig,which is mainly used for the treatment of type 2 diabetes mellitus(T2DM).In addition to acting as a glycosidase inhibitor in the small intestine after oral administration,SZ-A can also be absorbed into blood and widely distributed to target organs related to diabetes,exerting multiple pharmacological effects.It is important to elucidate the possible pharmacokinetic influences of SZ-A for its clinical rational applications,such as drug interactions,the effects of food and alcohol on the absorption of SZ-A.However,studies in this area are limited.Therefore,the pharmacokinetic interactions between orally administrated SZ-A(50 mg·kg^(-1))and metformin hydrochloride(Met,200 mg·kg^(-1))in Sprague-Dawley(SD)rats were examined.Then,the effect of food(standard feed)on the pharmacokinetics of SZ-A was investigated using fasting administration of SZ-A(50 mg·kg^(-1))in rats as a control.Finally,we investigated the pharmacokinetic characteristics of SZ-A(50 mg·kg^(-1))in different concentrations alcohol solutions using aqueous solution of SZ-A administered to rats as a control to evaluate the effect of alcohol on the bioabsorption of SZ-A.The results showed no significant pharmacokinetic interactions between SZ-A and Met after combination treatment.The standard feed had little effect on the pharmacokinetic profile of SZ-A.Alcohol retarded the absorption of SZ-A,resulting in a significant decrease in the Cmax of SZ-A.The decrease was greater at higher alcohol concentrations;however,no significant difference was observed in the AUC0-t.These results support the clinical rational applications of SZ-A.All animal protocols were approved by the Ethics Committee of Kangtai Medical Laboratory Service Hebei Co.,Ltd.(Hebei,China)(No.MDL2022-01-17-1).

关 键 词：桑枝总生物碱 盐酸二甲双胍 药物相互作用 药代动力学 食物和乙醇 

分 类 号：R917[医药卫生—药物分析学]