Advanced Oxidation Protein Products Regulate the Pharmacokinetics of Aloe-emodin, Emodin, Rhein, and Chrysophanol in Chronic Kidney Disease Rats

Abstract

Background

As accelerators and products of the progression of chronic kidney disease (CKD), advanced oxidation protein products (AOPPs) affect the function of the liver. Huang Gan granules (HGGs) are commonly used to prevent the progression of CKD, but the pharmacokinetics of aloe-emodin, emodin, rhein, and chrysophanol in HGGs in CKD remain unknown.

Objective

To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin, emodin, rhein, and chrysophanol in HGGs.

Methods

We constructed 5/6 nephrectomised (5/6 nx), adenine-induced (adenine) and AOPP-treated rat models. After oral administration of HGG, the concentrations of aloe-emodin, emodin, rhein, and chrysophanol in the plasma samples were detected by high-performance liquid chromatography (HPLC), and their pharmacokinetics were analysed with the PKSolver software. The plasma concentrations of IL-6 and TNF-α are detected by enzyme linked immunosorbent assay (ELISA). The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-α and IL-6 on the mRNA expression of CYP1A2 and CYP3A4.

Result

The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear (R² > 0.9931), precision (< 9.4%) and accuracy (± 10%). In 5/6 nx, adenine and AOPPs-treated rats, the concentrations of TNF-α and IL-6 were increased. In 5/6 nx and adenine rats, the pharmacokinetic parameters (t_1/2, MRT_0-∞ and AUC_0-∞) of aloe-emodin, emodin, rhein, and chrysophanol were, respectively, significantly increased and correlated with the concentration of AOPPs. In AOPPs-treated rats, the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.

Conclusion

In summary, inflammatory cytokine production may be one of the important causes in AOPPs' regulating the pharmacokinetic of aloe-emodin, emodin, rhein, and chrysophanol in the CKD rats. Studies of aloe-emodin, emodin, rhein, and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.