Astragalus injection alters the pharmacokinetics of doxorubicin and affects the activity of CYP450 enzymes

Abstract

Abstract Background Doxorubicin (DOX) is an antitumor antibiotic widely used in the treatment of breast cancer, liver cancer, lymphoma and other malignant tumors. However, its clinical application is limited by the side effects and drug resistance. Astragalus injection has been combined with DOX in the treatment of cancer, which can improve the curative effect and reduce drug resistance. This study investigated the interaction between DOX and Astragalus injection and elucidated the potential mechanism. Methods The pharmacokinetics of DOX injection (7 mg/kg) with or without Astragalus injection (4.25 mL/kg/day for 14 days) were investigated in male Sprague-Dawley rats (n = 6) by UPLC-MS/MS. The group without the Astragalus injection was set as the control group. Additionally, Sprague-Dawley rat liver microsomes incubation systems were employed to assess the effects of Astragalus injection on CYP450 enzymes. Results Astragalus injection significantly increased the Cmax (2090.01 ± 99.60 vs. 5262.77 ± 111.15 ng/mL) and AUC0-t (1190.23 ± 104.43 vs. 3777.27 ± 130.55 µg/L × h) and prolonged the t1/2α (0.09 ± 0.02 vs. 0.14 ± 0.04 h) of DOX. Astragalus injection significantly inhibited the activity of CYP1A2, CYP2C9, CYP2E1, and CYP3A4, and enhanced the activity of CYP2D1 with a metabolic elimination rate of 30.11 ± 2.67% vs 19.66 ± 3.41%, 35.95 ± 2.57% vs 23.26 ± 3.57%, 13.43 ± 2.56% vs 9.06 ± 2.51%, 47.90 ± 6.30% vs 25.87 ± 2.55%, 17.62 ± 1.49% vs 24.12 ± 2.91%, respectively (p < 0.05). Conclusions The co-administration of DOX and Astragalus injection alters the system exposure of DOX, possibly by affecting the metabolism of DOX by affecting the activity of CYP450 enzymes. Further clinical studies could be carried out according to the investigation.