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Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and Nonalcoholic Fatty Liver Disease Rats

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats.

Methods

This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography–ultraviolet.

Results

The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0 → ∞) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (Tmax), terminal elimination half-life (t1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05).

Conclusions

This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.

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Reference

  1. Di Ciaula A, Bonfrate L, Krawczyk M, Fruhbeck G, Portincasa P. Synergistic and detrimental effects of alcohol intake on progression of liver steatosis. Int J Mol Sci. 2022;23(5):2636.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Alqahtani SA, Schattenberg JM. NAFLD in the elderly. Clin Interv Aging. 2021;16:1633–49.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Berk K, Bzdega W, Konstantynowicz-Nowicka K, Charytoniuk T, Zywno H, Chabowski A. Phytocannabinoids—a green approach toward non-alcoholic fatty liver disease treatment. J Clin Med. 2021;10(3):393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marchesini G, Taylor R. Genes and lifestyle: which of the two is more relevant in driving NAFLD progression? Dig Liver Dis. 2021;53(11):1433–4.

    Article  PubMed  Google Scholar 

  5. Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int. 2017;37(Suppl 1):97–103.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lassailly G, Caiazzo R, Pattou F, Mathurin P. Perspectives on treatment for nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1835–48.

    Article  PubMed  Google Scholar 

  7. Yin X, Guo X, Liu Z, Wang J. Advances in the diagnosis and treatment of non-alcoholic fatty liver disease. Int J Mol Sci. 2023;24(3):2844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Colca J. NASH (nonalcoholic steatohepatitis), diabetes, and macrovascular disease: multiple chronic conditions and a potential treatment at the metabolic root. Expert Opin Investig Drugs. 2020;29(2):191–6.

    Article  CAS  PubMed  Google Scholar 

  9. Doumas M, Imprialos K, Stavropoulos K, Athyros VG. What does the future hold for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis? Curr Vasc Pharmacol. 2019;17(5):425–8.

    Article  CAS  PubMed  Google Scholar 

  10. Xiang H, Zuo J, Guo F, Dong D. What we already know about rhubarb: a comprehensive review. Chin Med. 2020;15:88.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cao YJ, Pu ZJ, Tang YP, Shen J, Chen YY, Kang A, et al. Advances in bio-active constituents, pharmacology and clinical applications of rhubarb. Chin Med. 2017;12:36.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhang F, Wu R, Liu Y, Dai S, Xue X, Li Y, et al. Nephroprotective and nephrotoxic effects of rhubarb and their molecular mechanisms. Biomed Pharmacother. 2023;160: 114297.

    Article  CAS  PubMed  Google Scholar 

  13. Yang M, Li X, Zeng X, Ou Z, Xue M, Gao D, et al. Rheum palmatum L. attenuates high fat diet-induced hepatosteatosis by activating AMP-activated protein kinase. Am J Chin Med. 2016;44(3):551–64.

    Article  CAS  PubMed  Google Scholar 

  14. Wu C, Bian Y, Lu B, Wang D, Azami NLB, Wei G, et al. Rhubarb free anthraquinones improved mice nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasome. J Transl Med. 2022;20(1):294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li P, Lu Q, Jiang W, Pei X, Sun Y, Hao H, et al. Pharmacokinetics and pharmacodynamics of rhubarb anthraquinones extract in normal and disease rats. Biomed Pharmacother. 2017;91:425–35.

    Article  CAS  PubMed  Google Scholar 

  16. Feng SX, Li JS, Qu LB, Shi YM, Zhao D. Comparative pharmacokinetics of five rhubarb anthraquinones in normal and thrombotic focal cerebral ischemia-induced rats. Phytother Res. 2013;27(10):1489–94.

    Article  CAS  PubMed  Google Scholar 

  17. Kulsharova G, Kurmangaliyeva A. Liver microphysiological platforms for drug metabolism applications. Cell Prolif. 2021;54(9): e13099.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Almazroo OA, Miah MK, Venkataramanan R. Drug metabolism in the liver. Clin Liver Dis. 2017;21(1):1–20.

    Article  PubMed  Google Scholar 

  19. Kollipara S, Bende G, Agarwal N, Varshney B, Paliwal J. International guidelines for bioanalytical method validation: a comparison and discussion on current scenario. Chromatographia. 2011;73(3–4):201–17.

    Article  CAS  Google Scholar 

  20. Gallagher J, Biesboer AN, Killian AJ. Pharmacologic issues in liver disease. Crit Care Clin. 2016;32(3):397–410.

    Article  PubMed  Google Scholar 

  21. Sahre MD, Guinn D, Ramamoorthy A, Kim I, Zhang X, Mehta R, et al. Assessing pharmacokinetics in liver disease: challenges and future considerations for classification of hepatic dysfunction and use of in silico methods. J Clin Pharmacol. 2023;63(7):755–8.

    Article  CAS  PubMed  Google Scholar 

  22. Zhu Y, Chen L, He Y, Qin L, Tan D, Bai Z, et al. The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice. Drug Metab Rev. 2023:1–18.

  23. Li YT, Wang L, Chen Y, Chen YB, Wang HY, Wu ZW, et al. Effects of gut microflora on hepatic damage after acute liver injury in rats. J Trauma. 2010;68(1):76–83.

    PubMed  Google Scholar 

  24. Fouts DE, Torralba M, Nelson KE, Brenner DA, Schnabl B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol. 2012;56(6):1283–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: a review. Curr Drug Targets. 2018;19(1):38–54.

    Article  CAS  PubMed  Google Scholar 

  26. Villatoro JM, García IG, Bueno D, de la Cámara R, Estébanez M, de la Guía AL, et al. Randomised multicentre clinical trial to evaluate voriconazole pre-emptive genotyping strategy in patients with risk of aspergillosis: vorigenipharm study protocol. BMJ Open. 2020;10(10): e037443.

    Article  Google Scholar 

  27. Rey-Bedon C, Banik P, Gokaltun A, Hofheinz O, Yarmush ML, Uygun MK, et al. CYP450 drug inducibility in NAFLD via an in vitro hepatic model: Understanding drug–drug interactions in the fatty liver. Biomed Pharmacother. 2022;146: 112377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang SS, Sheng FY, Zou L, Xiao JB, Li P. Hyperoside attenuates non-alcoholic fatty liver disease in rats via cholesterol metabolism and bile acid metabolism. J Adv Res. 2021;34:109–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166, Liu Tai Avenue, Wenjiang District, Chengdu, 611137, China

    Fang Zhang, Rui Wu, Yanfang Liu, Shu Dai, Xinyan Xue, Xiaohong Gong & Yunxia Li

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  1. Fang Zhang
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  2. Rui Wu
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  3. Yanfang Liu
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Corresponding authors

Correspondence to Xiaohong Gong or Yunxia Li.

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Author Contributions

Fang Zhang and Xiaohong Gong conducted the experiments. Fang Zhang and Xiaohong Gong wrote the manuscript and prepared the figures. Fang Zhang, Rui Wu, Yanfang Liu, and Shu Dai conducted the sample collection and data analysis. Yunxia Li conceived the study.

Funding

This study was supported by National Natural Science Foundation of China (grant nos. 82004052, 81891012 and U19A2010), Postdoctoral Science Foundation (grant no. 2021M692327), Sichuan Province Science and Technology Support Program (nos. 2021JDRC0041 and 22ZYZYTS0071), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (no. ZYYCXTD-D-202209).

Conflict of Interest

The authors (Fang Zhang, Rui Wu, Yanfang Liu, Shu Dai, Xiaohong Gong, Yunxia Li) declare no conflicts of interest.

Ethics Approval

All animal experiments were conducted strictly in accordance with ethical guidelines approved by the Animal Ethical Committee of Chengdu University of Traditional Chinese Medicine and handled according to the Management and Experimental Guidelines for Laboratory Animals of Chengdu University of Traditional Chinese Medicine (permit number: SYXK 2020-124, approval date: 04-12-2020). All institutional and national guidelines for the care of the laboratory animals were followed.

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Availability of Data and Materials

All data and materials are available from the corresponding author.

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Supplementary Information

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Zhang, F., Wu, R., Liu, Y. et al. Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and Nonalcoholic Fatty Liver Disease Rats. Eur J Drug Metab Pharmacokinet 49, 111–121 (2024). https://doi.org/10.1007/s13318-023-00875-z

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  • DOI: https://doi.org/10.1007/s13318-023-00875-z

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