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Metabolism, pharmacokinetics, and hepatic disposition of xanthones and saponins on Zhimu treatments for exploratively interpreting the discrepancy between the herbal safety and timosaponin A3-induced hepatotoxicity

Authors: Yang Xie1,2, Xu Zhou1,3, Hu Pe1,3, Ming-cang Che1,3, Zhao-lin Sun1,3, Ya-ru Xue1,3, Xiao-ting Tian1,3, Cheng-gang Huang1,3
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 Pharmacy Academy, Harbin University of Commerce, Harbin 150076, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Xiao-ting Tian: zhghydxtxt@163.com, Cheng-gang Huang: cghsimm@126.com,
DOI: 10.1038/s41401-018-0012-z
Received: 11 December 2017
Accepted: 31 January 2018
Advance online: 23 May 2018

Abstract

Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.
Keywords: Zhimu; timosaponin A3; mangiferin; pharmacokinetics; metabolism; hepatotoxicity; antioxidant

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