塔克林
药理学
肠道菌群
基于生理学的药代动力学模型
拟杆菌
药代动力学
生物
医学
生物化学
酶
细菌
遗传学
乙酰胆碱酯酶
作者
Lian Yee Yip,Chiu Cheong Aw,Sze Han Lee,Yi Hong,Han Chen Ku,Winston Hecheng Xu,Jessalyn Mei Xuan Chan,Eleanor Jing Yi Cheong,Kern Rei Chng,Amanda Hui Qi Ng,Niranjan Nagarajan,Ratha Mahendran,Yuan Kun Lee,Edward R. Browne,Eric Chun Yong Chan
出处
期刊:Hepatology
[Wiley]
日期:2017-11-19
卷期号:67 (1): 282-295
被引量:76
摘要
The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver–gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine‐induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3‐fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine‐induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus , Bacteroides , and Enterobacteriaceae ) and approximately 9% higher β‐glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β‐glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine‐induced transaminitis in vivo . Conclusion: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (H epatology 2018;67:282‐295).
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