The pharmacokinetics effects of MCAO model on senkyunolide I in pseudo germ-free rats after oral co-administration of Chuanxiong and warfarin

Haigang Li^1*Fang Li²Yi Zhou³Zhongjun Xiang²Bilan Zhou⁴Bin Lan²Xiaoling Ruan⁵

• ¹Hunan key laboratory of the research and development of novel pharmaceutical preparations, Changsha Medical University, Changsha, Anhui Province, China
• ²Changsha Medical University, Changsha, Hunan Province, China
• ³College of Pharmacy, Changsha Medical University, Changsha, Hunan Province, China
• ⁴Changsha Health Vocational College, Changsha, Hunan Province, China
• ⁵Hunan Polytechnic College of Environment and Biology, Hengyang, Hunan Province, China

Aim: To investigate the pharmacokinetics effects of middle cerebral artery occlusion (MCAO) model on senkyunolide I (SEI) in pseudo germ-free rats after oral coadministration of Chuanxiong and warfarin. Methods: Rats were divided randomly into WC_H, WS_H, WC_HF, WS_HF, WC, WS, WC_F and WS_F groups (W, warfarin; C, Chuanxiong; S, SEI; H, rats without MACO operation; F, pseudo germ-free), pseudo germ-free rats were orally administrated of ciprofloxacin hydrochloride (50 mg/kg, twice a day) consecutive 3 day first, MCAO operation was carried on the third day, Chuanxiong (10 g/kg) or SEI (7.5 mg/kg) and warfarin sodium (0.5 mg/kg) were orally administrated only once on the fourth day. The plasma concentrations of SEI were determined by UPLC-MS/MS. And the stool samples were collected for gut microbiota analyses. The coronal thin slices of brain were dyed by triphenyl-2H-tetrazolium chloride. Results: Compared to the WC_H group, the AUC0-t and Cmax of the WC group increased 2.08 and 1.79 fold (P < 0.001). Compared with the WS_H group, the AUC0-t and Cmax of the WS group decreased to 6.24 and 22.64 percent (P < 0.001). Compared to the WC_HF group, the AUC0-t and t1/2z of the WC_F group decreased to 60.95 and 35.26 % (P < 0.01). Compared with the WS_HF group, the AUC0-t and Cmax of the WS_F group decreased to 2.87 and 8.54 percent (P < 0.001). Compared to the WC_H group, the AUC0-t and Cmax of the WC_HF group increased 85.03 and 82.48 percent (P < 0.001). Compared with the WS_H group, the AUC0-t and Cmax of the WS_HF group increased 1.40 and 2.43 fold (P < 0.001). Compared to the WC group, the AUC0-t and t1/2z of the WC_F group decreased 45.81 and 79.44 percent (P < 0.001). Compared with the WS group, the AUC0-t and t1/2z of the WS_F group decreased 35.86 and 79.74 percent (P < 0.001). Both MCAO operation and pseudo germ-free condition significantly changed the pharmacokinetics characteristic of SEI after oral co-administration of warfarin and Chuanxiong or SEI. It is a promising way to understand the potential pharmacokinetics herb-drug interactions from the angle of gut microbiota.