Mechanisms Underlying the Differences in the Pharmacokinetics of Six Active Constituents of Huangqi Liuyi Decoction between Normal and Diabetic Nephropathy Mouse Models

Abstract

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.

Study on the liver Drug’s dominant metabolic enzymes for six effective components of the Huang qi Liuyi decoction

“…The pathogenesis of this model is very similar to that of human type 2 diabetes mellitus. After 4 weeks of age, this mouse strain gradually develops diabetic signs such as obesity, glycosuria, hyperglycemia, and hyperlipidemia, whereas complications of diabetic nephropathy occur at 8-12 weeks of age (Ponchiardi et al, 2013;Wang et al, 2022c). A previous study by our group found that blood glucose, triglycerides, cholesterol, blood creatinine, urea nitrogen, and 24-h urinary protein were significantly higher in 12-week-old db/db mice compared to control (p < 0.05).…”

“…The study also discovered no statistical difference between the efficacy of Huangqi Liuyi decoction and HQD in mice with diabetic nephropathy (Wang et al, 2022b). According to pharmacokinetic studies, mice with diabetic nephropathy exhibited greater absorption and delayed elimination of the six effective components (astragaloside IV, glycyrrhizic acid, calycosin-glucuronide, formononetin, ononin, calycosin-7-O-β-D-glucoside) following oral administration HQD (Wang et al, 2022c).…”