Plasma Pharmacokinetics and Tissue Distribution of Doxorubicin in Rats following Treatment with Astragali Radix

Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg x 1 or x 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein-protein interactome. We found that short-term (<= 10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration-time curve (AUC, 1303.35 +/- 271.74 mu g/L*h versus 1208.74 +/- 145.35 mu.g/L*h, p > 0.46), peak concentrations (C-max, 1351.21 +/- 364.86 mu.g/L versus 1411.01 +/- 368.38 mu.g/L, p > 0.78), and half-life (t(1/2), 31.79 +/- 5.12 h versus 32.05 +/- 6.95 h, p > 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p < 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.