Abstract
Objectives: The interaction between the components of traditional Chinese medicine (TCM) is an important basis for their synergy. Rhein and curcumin exert various pharmacological activities, including anti-tumour, anti-inflammatory, antioxidant, anti-fibrosis and renoprotective effects. However, no investigation has reported the synergistic anti-fibrosis effect yet. This study aims at determine the pharmacokinetics and pharmacodynamics of the combination of rhein and curcumin in the treatment for chronic kidney disease in rats. Design: Fifty two male Sprague-Dawley (SD) rats were randomly divided into rhein group, curcumin group and their combination group for pharmacodynamics studies. HE and Masson staining was conducted to observe the changes of renal morphology. Kits were used to detect the level of urea nitrogen (BUN) and creatinine (Scr). For pharmacokinetic study, 36 SD rats were randomly divided into rhein group, curcumin group and a combination group, the content of rhein and curcumin in plasma and renal tissue was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In additon, molecular docking method and cell experiments was used to disclose the interaction mechanism between curcumin and rhein. Results: The pharmacodynamic results showed that the degree of renal fibrosis was improved obviously by co-administration rhein and curcumin. Meanwhile, compared to single administration, the Cmax and AUC of rhein and curcumin in plasma and renal tissue were enhanced significantly after co-administration. Moreover, the result of molecular docking and cell experiments showed that both two compounds could interact with P-gp, CYP2C9 and CYP2C19. Conclusion: Together, these findings demonstrated that rhein and curcumin had a synergistic effect in ameliorateing chonic kidney disease, providing an important explanation on the synergistic mechanism of curcumin and rhein from a pharmacokinetic viewpoint.
Highlights
According to epidemiological survey, the total prevalence of chronic kidney disease (CKD) in the world is 11% (Gansevoort et al, 2013; Xie et al, 2018)
In the Unilateral Ureteral Obstruct (UUO) group, there was an expansion of the renal interstitial space, an increase in interstitial cells, a deposition of collagen components, the appearance of vacuoles, lesions of tubular and the fibrosis of renal interstitial was observed from the 7th day after surgery operation
In coadministration group, the degree of renal fibrosis was improved more than that of rhein or curcumin groups, which suggested that the combination of rhein and curcumin could treat renal interstitial fibrosis and improve the degree of renal tissue damage more effectively
Summary
The total prevalence of chronic kidney disease (CKD) in the world is 11% (Gansevoort et al, 2013; Xie et al, 2018). Mainly derived from dried rhizome of Curcuma longa L, possesses multiple pharmacological abilities, including anticancer, anti-inflammatory, antioxidation, antifibrotic, antiarthritis (Hatcher et al, 2008; Azhdari et al, 2019), as well as a neuroprotective effect (Sun et al, 2017) Both rhein and curcumin have antifibrotic activity and have showed good efficacy to prevent the progress of renal fibrosis (Kuwabara et al, 2006; He et al, 2011; Soetikno et al, 2013; Zhou et al, 2014; Ho et al, 2016; Hu et al, 2016; Zhang et al, 2016; Chen et al, 2019b). Further investigation of the antifibrosis effect of rhein and curcumin was of great significance for the development of new antifibrosis drugs
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