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. (December 2018)

• Record Type: Journal Article
• Authors: Xie, Yang; Zhou, Xu; Pei, Hu; Chen, Ming-cang; Sun, Zhao-lin; Xue, Ya-ru; Tian, Xiao-ting; Huang, Cheng-gang
• Is Part Of: Acta pharmacologica Sinica. Volume 39:Number 12(2018)
• Page Start: 1923
• Page End: 1934
• Publication Date: 2018-12
• Subjects: Zhimu -- timosaponin A3 -- mangiferin -- pharmacokinetics -- metabolism -- hepatotoxicity -- antioxidant; Pharmacology -- Periodicals; 615.105
• DOI: 10.1038/s41401-018-0012-z
• Languages: English
• ISSNs: 1671-4083

Abstract

Abstract Timosaponin A3, a saponin inZhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication ofZhimu 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 onZhimu 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) onZhimu treatments. Consequently, following oral administration ofZhimu 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 inZhimu . The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes inZhimu 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 ofZhimu, 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 ofZhimu in the future.