Huangqi Liuyi decoction is a famous traditional Chinese medicine (TCM) that has been widely used in China for the management of diabetes since the Song Dynasty. Today, it is commonly used for treating diabetic nephropathy (DN). Our previous experimental studies have suggested that the mixture HQD, containing astragalus saponin, astragalus flavone, astragalus polysaccharide, and glycyrrhetinic acid, could be used for the treatment of DN and to improve renal function. The objective of this study was to develop a sensitive and reliable high-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantitation of astragaloside IV, calycosin-7-O-β-D-glucoside, calycosin-glucuronide, ononin, formononetin, and glycyrrhizic acid, which are the main active constituents in HQD, and to compare the pharmacokinetics of these active constituents in control and DN mice orally treated with HQD. The results indicated that the pharmacokinetic parameters of HQD were significantly different between the control and DN mouse groups. The absorption of HQD in the DN mice was greater than that in control mice.

The aim of this study was to explore the mechanisms underlying the differences in the pharmacokinetics of Huangqi Liuyi decoction extract (HQD) under physiological and pathological conditions. The roles of liver cytochrome P450 metabolic enzymes (Cyp450) and small intestinal transporters were also investigated. The cocktail probe drug method was used to investigate the effects of diabetic nephropathy (DN) and HQD on metabolic enzyme activity. The expression levels of liver Cyp450 metabolic enzymes (Cyp1A2, Cyp2C37, Cyp3A11, Cyp2E1, and Cyp2C11) and small intestinal transporters (breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporters (OCTs), and multidrug resistance-associated protein (MRPs) were determined using western blot. Compared to normal mice, the expression of OCT1, OCT2, MRP1, and MRP2 was increased in DN mice, while that of P-gp and BCRP ( P < 0.05 and P < 0.001 ) was inhibited. HQD inhibited expression of Cyp1A2 and Cyp3A11 and increased the expression of P-gp and BCRP in normal mice. In DN mice, HQD induced expression of BCRP and inhibited expression of Cyp2C37, Cyp3A11, OCT2, MRP1, and MRP2. The activity of each Cyp450 enzyme was consistent with changes in expression. The changes in pharmacokinetic parameters of HQD in DN might, in part, be secondary to decreased expression of P-gp and BCRP. HQD varied in regulating transporter activities between health and disease. These findings support careful application of HQD-based treatment in DN, especially in combination with other drugs.

The purpose of this study was to investigate the effects of Huangqi Liuyi decoction extract (HQD) on diabetic nephropathy (DN), and the tissue distribution difference of six main active ingredients of HQD between normal and DN mouse models. DN mice were administered HQD for 12 weeks to investigate its efficacy in the treatment of DN. Liquid chromatography-tandem mass-spectrometry (HPLC-MS/MS) was used to analyze the tissue distribution of the six active ingredients of HQD in normal and DN mice, including astragaloside IV, calycosin-7-O-β-D-glucoside, calycosin glucuronide, ononin, formononetin, and glycyrrhizic acid. DN mice treated with HQD showed significantly decreased fasting blood glucose (FBG), 24-h urinary protein (24 h U-Alb), blood urea nitrogen (BUN), serum creatinine (Scr), and triglyceride levels (TG) (p &lt; 0.05). Moreover, there were no significant differences in pharmacodynamics between HQD and Huangqi Liuyi decoction. Treated mice also had decreased expression of collagen I, ɑ–smooth muscle actin (ɑ-SMA), and vimentin; and upregulated expression of E-cadherin in their kidneys. Compared to normal mice, distributions of the six ingredients in the liver, heart, spleen, lungs, kidneys, stomach, small intestine, brain, and muscle of DN mice were different. The results indicated that the HQD could be used for the treatment of DN and to improve renal function. The pathological state of diabetic nephropathy may affect tissue distribution of HQD active ingredients in mice.

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