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.

17Objective Morinidazole is a novel third generation 5-nitroimidazole antimicrobial 18 drug which has demonstrated substantial antibacterial activity against clinical isolates 19 of anaerobe. The aim of this study was to build population pharmacokinetic (PPK) 20 model of morinidazole among patients with hepatic impairment and to provide dosage 21 adjustment strategy for morinidazole in patients with hepatic impairment and/or renal 22 2 dysfunction. 23 Methods The nonlinear mixed effects modeling tool NONMEM (version7.3, ICON 24 Development Solutions) was used to develop the PPK model of morinidazole. 25Results One-compartment model was conducted to establish the morinidazole PPK 26 model. Disease condition was the significant covariate for CL and weight was the 27 significant covariate for V. The AUC 0-∞ was 120.44±37. 05 (79.25-207.20) μg×h/mL 28 in hepatic impairment group and was 79.46±23.71 (42.94-116.75) μg×h/mL in control 29 group. The AUC 0-∞ was 164.9±44.8 μg×h/mL and 77.2±23.1 μg×h/mLin in the 3 30 subjects with both hepatic impairment and mild renal impairment and in the 3 31 matched healthy subjects，respectively. 32 Conclusion It is not necessary to adjust morinidazole dosage for patients with 33 moderate hepatic impairment without confirmed renal dysfunction. For patient with 34 moderate hepatic and mild renal impairment, morinidazole regimen should be 35 considered as 500mg every 24 hours. When used in patients with moderate/severe 36 hepatic impairment combined with renal dysfunction, both dosage and interval 37 adjustment of morinidazole should be considered.38 Introduction 39 Morinidazole is a novel third generation 5-nitroimidazole antimicrobial drug 40 which has demonstrated substantial antibacterial activity against clinical isolates of 41 anaerobe including gram negative Sporeless bacterium and gram-positive coccus 42 based on the result of pharmacodynamics study in vitro. The antibacterial activity of 43 morinidazole against Bacteroides fragilis, Veillonella and Clostridium perfringens is 44 3comparable to that of ornidazole, which is 2 to 8 times stronger than that of 45 metronidazole and tinidazole. The antibacterial activity of morinidazole against 46 Bacteroides distasonis and Bacteroides ovatus is comparable to that of ornidazole, 47 which is 2 to 8 times stronger than that of metronidazole and tinidazole as well (1, 2). 48Morinidazole and Sodium Chloride Injection was approved by CFDA in February 49 2014 for the treatment of pelvic inflammatory disease caused by Peptostreptococcus, 50 Bacteroides fragilis, Veillonella and Bacteroides distasonis, suppurative appendicitis 51 and gangrenous appendicitis caused by anaerobes (3). 52Morinidazole showed a positively correlated relationship between dosage and 53 AUC 0-t as well as C max . The V ss of morinidazole was 1209±158 mL/kg after infusion 54 at 16mg/kg for 2h. The human plasma protein binding rate of morinidazole was 22.1 55 to 27.2%. Morinidazole was widely distributed in tissues and body fluids.56 Morinidazole was mainly metabol...