Yuting Yang1, Jiehong Yang1, Wei Fu2, Peng Zhou1, Yu He1, Mingsun Fang1, Haitong Wan3, Huifen Zhou4. 1. Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China. 2. Buchang Pharmaceutical Co., Ltd., Xi'an, 710075, People's Republic of China. 3. Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China. whtong@126.com. 4. Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China. zhouhuifen2320@126.com.
Abstract
BACKGROUND AND OBJECTIVES: Guanxinshutong capsules (GXST) are usually used to treat acute myocardial infarction (AMI), and the clinical effect of GXST is significant. However, there have been only a few studies on the pharmacokinetics of GXST against AMI injury. The objective of this study was to investigate the pharmacokinetics of nine bioactive compounds of GXST in normal and AMI rats. METHODS: In this work, a rat model of AMI was established by ligating the left anterior descending coronary artery. The pharmacokinetic parameters of nine bioactive compounds (gallic acid, danshensu, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B and salvianolic acid A, dihydrotanshinone I, cryptotanshinone, and tanshinone IIA) in the plasma of AMI and normal rats were compared under the same dose of GXST by a LC-MS/MS method. Then, we selected P-glycoprotein (P-gp) and some representative cytochrome P450 enzymes (CYPs) for molecular docking to further analyze the interaction between these compounds. RESULTS: The pharmacokinetic studies showed that the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of phenolic acids were relatively large, while the half-life (T½) of tanshinones was longer. Among the nine components, salvianolic acid B in AMI rats had the maximum area under the concentration-time curve (AUC0-∞ = 1961.8 ng·h/mL), which showed a significant difference compared with normal rats (P < 0.05). Tanshinone IIA in AMI rats had the longest half-life (T½ = 10.1 h), and it was markedly longer than that in normal rats (P < 0.01). In addition, compared with the normal group, the AUC, Cmax, T½ , and time to reach Cmax (Tmax) of gallic acid increased significantly in AMI rats (P < 0.05 or P < 0.01). For the molecular docking results, it was found that gallic acid may interact with CYP1A2, CYP2D6, and CYP2C9, while danshensu may interact with CYP2C9. Tanshinones may interact with CYP1A2, CYP2D6, CYP2C9, and P-gp. CONCLUSIONS: The results suggest that the pathological injury caused by AMI has a significant impact on the pharmacokinetic characteristics of some active compounds in GXST, which are conducive to providing a reference and promoting rational clinical drug use.
BACKGROUND AND OBJECTIVES: Guanxinshutong capsules (GXST) are usually used to treat acute myocardial infarction (AMI), and the clinical effect of GXST is significant. However, there have been only a few studies on the pharmacokinetics of GXST against AMI injury. The objective of this study was to investigate the pharmacokinetics of nine bioactive compounds of GXST in normal and AMI rats. METHODS: In this work, a rat model of AMI was established by ligating the left anterior descending coronary artery. The pharmacokinetic parameters of nine bioactive compounds (gallic acid, danshensu, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B and salvianolic acid A, dihydrotanshinone I, cryptotanshinone, and tanshinone IIA) in the plasma of AMI and normal rats were compared under the same dose of GXST by a LC-MS/MS method. Then, we selected P-glycoprotein (P-gp) and some representative cytochrome P450 enzymes (CYPs) for molecular docking to further analyze the interaction between these compounds. RESULTS: The pharmacokinetic studies showed that the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of phenolic acids were relatively large, while the half-life (T½) of tanshinones was longer. Among the nine components, salvianolic acid B in AMI rats had the maximum area under the concentration-time curve (AUC0-∞ = 1961.8 ng·h/mL), which showed a significant difference compared with normal rats (P < 0.05). Tanshinone IIA in AMI rats had the longest half-life (T½ = 10.1 h), and it was markedly longer than that in normal rats (P < 0.01). In addition, compared with the normal group, the AUC, Cmax, T½ , and time to reach Cmax (Tmax) of gallic acid increased significantly in AMI rats (P < 0.05 or P < 0.01). For the molecular docking results, it was found that gallic acid may interact with CYP1A2, CYP2D6, and CYP2C9, while danshensu may interact with CYP2C9. Tanshinones may interact with CYP1A2, CYP2D6, CYP2C9, and P-gp. CONCLUSIONS: The results suggest that the pathological injury caused by AMI has a significant impact on the pharmacokinetic characteristics of some active compounds in GXST, which are conducive to providing a reference and promoting rational clinical drug use.