Pharmacokinetics and metabolism of trans-emodin dianthrones in rats

• Published in: Journal of ethnopharmacology Vol. 290; p. 115123
• Main Authors: Song, Yunfei, Yang, Jianbo, Wang, Xueting, Chen, Junmiao, Si, Dandan, Gao, Huiyu, Sun, Mingyi, Cheng, Xianlong, Wei, Feng, Ma, Shuangcheng
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 23.05.2022
• Subjects: Administration, Oral; Animals; Anthracenes - chemistry; Anthracenes - pharmacokinetics; Area Under Curve; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin - blood; Emodin - chemistry; Emodin - pharmacokinetics; Emodin - urine; Fallopia multiflora; Feces - chemistry; Half-Life; Male; Medicine, Chinese Traditional; Metabolic Clearance Rate; Metabolic transformation; Pharmacokinetics; Polygonum multiflorum Thunb; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Trans-emodin dianthrones; Polygonum multiflorum Thunb; Metabolic transformation; Pharmacokinetics; Trans-emodin dianthrones
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2022.115123

Polygonum multiflorum Thunb. (PM) is a common traditional Chinese medicine with diverse biological activities of resolving toxins, nourishing livers and promoting hairs. Nevertheless, in recent years hepatotoxic adverse reactions caused by the administration of PM have raised worldwide concerns. In our previous study, we found that emodin dianthrones showed hepatotoxicity and may be potential toxicity markers. However, the metabolic transformation and pharmacokinetic behavior of emodin dianthrones in vivo have still not been elucidated. Taking trans-emodin dianthrones (TED) as an example, the present study was conducted to investigate the pharmacokinetics and bioavailability of TED in rats and characterized its metabolic transformation in the plasma, urine and feces of rats. A rapid and sensitive UPLC-qqq-MS/MS method was developed for accurate quantification of TED in plasma and successfully applied to the pharmacokinetic evaluation of TED in rats after intravenous and oral administration. A reliable UFLC-Q-TOF-MS high resolution mass spectrometry combined with a scientific metabolite identification strategy was used to comprehensively characterize the metabolic transformation of TED in plasma, urine and feces in rats. The established UPLC-qqq-MS/MS method had a linear range of 1–500 ng/mL, and the method was accurate and reliable to meet the quantitative requirements. When 20 mg/kg TED was given by gavage rats, it was rapidly absorbed into the circulatory system and had a long half-life time of 6.44 h and wide tissue distribution in vivo. While intravenous injection of 0.4 mg/kg TED in rats, it was rapidly metabolized and eliminated with a half-life time of 1.82 h. The oral absorption bioavailability of TED was only 2.83%. Furthermore with a sensitive UFLC-Q-TOF-MS technique and metabolite identification strategy, 21 metabolites were successfully identified, including 11 in plasma, 12 in urine and 18 in feces. The main Ⅰ and Ⅱ phase metabolic processes involved glucuronidation, oxidation, carbonylation, (de)methylation, sulfation and hydrogenation. TED could be rapidly absorbed into the blood circulation and widely distributed and slowly metabolized in the body and underwent extensive cleavage and metabolic transformation in vivo. The study provided a basis for in-depth elucidation of the toxicology and mechanism research of TED, but also laid the foundation for further research on the material basis of hepatotoxicity of PM. [Display omitted] •Study the pharmacokinetics and bioavailability of the potential toxic marker TED in Polygonum multiflorum for the first time•A sensitive UPLC-MS/MS method was successfully constructed to determine the content of TED in plasma with the LOD of 1 ng/ml•First comprehensively elucidate the metabolic transformation of TED in plasma, urine and feces in rats•Twenty-one Ⅰ and Ⅱ phase metabolites were revealed by UFLC-Q-TOF-MS and a stepwise identification strategy