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.
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This work was supported by the National Key R&D Program of China (No.2017YFC1700400, 2017YFC1700403), and the Key Laboratory of TCM Encephalopathy of Zhejiang Province (No. 2020E10012).
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The authors declare no conflicts of interest.
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Animal welfare and experiments were strictly in accordance with the Regulation for the Administration of Affairs Concerning Experimental Animals (State Science and Technology Commission, 1988) and approved by the Institutional Animal Care and Use Committee (IACUC), ZJCLA, (Hangzhou, China).
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HW, YH, and HZ conceived the idea and designed the study. WF participated in the data collecting. YY and PZ participated in the experimental study and statistical analysis. MF established the acute myocardial infarction model in rats. YY and JY wrote the manuscript. All authors read and approved the final manuscript.
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Huifen Zhou and Haitong Wan are co-corresponding authors.
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Yang, Y., Yang, J., Fu, W. et al. Pharmacokinetic Comparison of Nine Bioactive Compounds of Guanxinshutong Capsule in Normal and Acute Myocardial Infarction Rats. Eur J Drug Metab Pharmacokinet 47, 653–665 (2022). https://doi.org/10.1007/s13318-022-00777-6
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DOI: https://doi.org/10.1007/s13318-022-00777-6