Original articles
Jian Li, Olajide E. Olaleye, Xuan Yu, Weiwei Jia, Junling Yang, Chuang Lu, Songqiao Liu, Jingjing Yu, Xiaona Duan, Yaya Wang, Kai Dong, Rongrong He, Chen Cheng, Chuan Li. High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1035-1049

High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care
Jian Lia,b, Olajide E. Olaleyea, Xuan Yua,b, Weiwei Jiaa, Junling Yanga, Chuang Luc, Songqiao Liud, Jingjing Yue, Xiaona Duana, Yaya Wanga, Kai Dongf, Rongrong Hea, Chen Chenga, Chuan Lia,b
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
b University of Chinese Academy of Sciences, Beijing 100049, China;
c Department of DMPK, Sanofi, Waltham, MA 02451, USA;
d Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China;
e School of Pharmacy, University of Washington, Seattle, WA 98105, USA;
f Tianjin Chasesun Pharmaceutical Co. Ltd., Tianjin 301700, China
Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibioticbased sepsis care. Although adding XueBiJing further reduced 28-day mortality via modulating the host response, pharmacokinetic herbedrug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing-antibiotic and antibiotic-XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.
Key words:    XueBiJing    Antibiotic    Combination drug therapy    Sepsis    Pharmacokinetic compatibility    Herb-drug interaction   
Received: 2019-02-13     Revised: 2019-04-22
DOI: 10.1016/j.apsb.2019.06.003
Funds: We thank Professor Chung S. Yang from Rutgers, The State University of New Jersey, Professor Ge Lin from The Chinese University of Hong Kong (China), and Professor Su Zeng from Zhejiang University (China) for reviewing and helping improve the manuscript. This work was funded by grants from the National Science & Technology Major Project of China "Key New Drug Creation and Manufacturing Program" (2017ZX09301012006), the National Basic Research Program of China (2012CB518403), the National Natural Science Foundation of China (81503345), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050306).
Corresponding author: Chen Cheng, Chuan Li     Email:chengchen@simm.ac.cn;chli@simm.ac.cn
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Jian Li
Olajide E. Olaleye
Xuan Yu
Weiwei Jia
Junling Yang
Chuang Lu
Songqiao Liu
Jingjing Yu
Xiaona Duan
Yaya Wang
Kai Dong
Rongrong He
Chen Cheng
Chuan Li

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