药学学报, 2021, 56(5): 1416-1423
引用本文:
周明皓, 张敏, 张硕, 王鹏娇, 孟小夏, 曹思源, 杨七妹, 高秀丽. 不同相对分子质量的聚乙二醇对黄芩苷药代动力学的影响[J]. 药学学报, 2021, 56(5): 1416-1423.
ZHOU Ming-hao, ZHANG Min, ZHANG Shuo, WANG Peng-jiao, MENG Xiao-xia, CAO Si-yuan, YANG Qi-mei, GAO Xiu-li. Effect of molecular weight of polyethylene glycol on pharmacokinetics of baicalin[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1416-1423.

不同相对分子质量的聚乙二醇对黄芩苷药代动力学的影响
周明皓1,3, 张敏1, 张硕2, 王鹏娇1, 孟小夏1,3, 曹思源1,3, 杨七妹1,3, 高秀丽1,3*
1. 贵州医科大学药用植物功效与利用国家重点实验室/药学院, 贵州 贵阳 550025;
2. 贵州医科大学实验动物中心, 贵州 贵阳 550025;
3. 贵州医科大学微生物与生化药学工程中心, 贵州 贵阳 550025
摘要:
本文旨在考察不同相对分子质量(MW:400、1 000、4 000)的药用辅料聚乙二醇(PEGs)对黄芩苷药代动力学的影响,并初步分析其作用机制。分别给大鼠灌胃相应的黄芩苷(168 mg·kg-1)+水溶液和黄芩苷+PEGs溶液,收集给药后0~24 h内的血浆,使用UPLC-MS/MS测定不同时间点黄芩苷及其主要代谢物黄芩素6-O-β-D-葡萄糖醛酸苷(B6G)在血浆内的浓度,并以DAS 3.0软件求算药代动力学参数。基于体外代谢酶孵育法探究不同相对分子质量的PEGs对尿苷二磷酸葡萄糖醛酸转移酶1A8(UGT1A8)和尿苷二磷酸葡萄糖醛酸转移酶1A9(UGT1A9)活性的影响。不同相对分子质量的PEGs与黄芩苷共给药后,显著提高了黄芩苷及B6G的AUC0-t,同时使Cmax升高,t1/2延长,结果表明PEGs能有效提高黄芩苷及B6G的体内浓度,其机制可能为不同相对分子质量的PEGs能够促进UGT1A8和UGT1A9的活性,使得黄芩苷和B6G的转化速率提升,其中对B6G的促进程度高于原型药物黄芩苷,表明PEGs对UGT1A8具有更高的亲和力,其中以PEG400的作用最为显著。本研究以期对黄芩苷等黄酮类药物的临床安全用药及PEGs参与的药物新剂型的设计提供依据。本研究中动物实验方案已获得贵州医科大学实验动物伦理委员会的批准。
关键词:    聚乙二醇      黄芩苷      黄芩素6-O-β-D-葡萄糖醛酸苷      尿苷二磷酸葡萄糖醛酸转移酶1A8      尿苷二磷酸葡萄糖醛酸转移酶1A9      药代动力学     
Effect of molecular weight of polyethylene glycol on pharmacokinetics of baicalin
ZHOU Ming-hao1,3, ZHANG Min1, ZHANG Shuo2, WANG Peng-jiao1, MENG Xiao-xia1,3, CAO Si-yuan1,3, YANG Qi-mei1,3, GAO Xiu-li1,3*
1. State Key Laboratory of Functions and Applications of Medicinal Plants and School of Pharmacy, Guizhou Medical University, Guiyang 550025, China;
2. Experimental Animal Center of Guizhou Medical University, Guiyang 550025, China;
3. Center of Microbiology and Biochemical Pharmaceutical Engineering, Guizhou Medical University, Guiyang 550025, China
Abstract:
The aim of this study was to investigate the effects of polyethylene glycol (PEGs) with different molecular weights (MW:400, 1 000, 4 000) on the pharmacokinetics of baicalin, and preliminarily analyze its mechanism. Rats were gavaged with baicalin (168 mg·kg-1) + aqueous solution or baicalin + PEGs solution and plasma samples were collected from 0 to 24 h after administration. The concentration of baicalin and its main metabolite baicalein 6-O-β-D-glucuronide (B6G) were determined at different time points by UPLC-MS/MS, and the pharmacokinetic parameters were calculated with DAS 3.0 software. The results showed that PEGs with different molecular weights could effectively increase the AUC0-t of baicalin and B6G, increase the Cmax, and prolong the t1/2, effectively increasing the concentration of baicalin and B6G in vivo. The mechanism may be by promoting the activity of uridine diphosphate glucuronosyl-transferases 1A8 (UGT1A8) and 1A9 (UGT1A9), thereby increasing the transformation rate of baicalin and B6G. The rate of metabolism of B6G was faster than that of baicalin, suggesting that PEGs had a higher affinity for UGT1A8, and PEG400 had the most significant effect. The purpose of this study was to provide a basis for the clinical safe use of baicalin and other flavonoids and the design of new dosage forms with the participation of PEGs. The animal experiment protocol in this study was approved by the Experimental Animal Ethics Committee of Guizhou Medical University.
Key words:    polyethylene glycol    baicalin    baicalein 6-O-β-D-glucuronide    uridine diphosphate glucuronosyl-transferases 1A8    uridine diphosphate glucuronosyl-transferases 1A9    pharmacokinetics   
收稿日期: 2020-11-03
DOI: 10.16438/j.0513-4870.2020-1688
基金项目: 国家自然科学基金资助项目(81160413);贵州省农业重大产业科学研究攻关项目(黔教合KY字[2019]009).
通讯作者: 高秀丽,Tel:86-851-88416153,E-mail:gaoxl@gmc.edu.cn
Email: gaoxl@gmc.edu.cn
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