Prediction of the drug-drug interaction between sodium tanshinone ⅡA sulfonate and clopidogrel based on the PBPK model
- VernacularTitle:基于PBPK模型预测丹参酮ⅡA磺酸钠与氯吡格雷联用的药物相互作用
- Author:
Die ZHANG
1
;
Lichao ZHANG
1
;
Mengru SUN
1
;
Fengdan QIAN
1
Author Information
1. Dept. of Pharmacy，Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201800，China
- Publication Type:Journal Article
- Keywords:
clopidogrel;
sodium tanshinone ⅡA sulfonate;
PBPK model;
drug-drug interaction;
clopidogrel thiol H4;
influencing factor
- From:
China Pharmacy
2026;37(13):1746-1750
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To develop physiologically based pharmacokinetic （PBPK） model for sodium tanshinone Ⅱ A sulfonate （STS）， clopidogrel （Clo）， and its metabolites， to predict the potential drug-drug interaction （DDI） between STS and Clo during co-administration， and to identify the key factors influencing the predicte d DDI， and provide evidence for rational clinical medication. METHODS Physicochemical and pharmacokinetic parameters of Clo， its metabolites， and STS were retrieved from PubMed， DrugBank， and SwissADME for PBPK model development. The steady-state area under the plasma concentration-time curve （AUC） and maximum concentration （ c max ） of clopidogrel thiol H4 （Clo-AM） were used as indicators to evaluate the DDI between STS and Clo. Single-factor sensitivity analysis was performed to identify key parameters influencing DDI between STS and Clo during co-administration. RESULTS Compared with Clo alone， after 7 days of Clo combined with STS 40 mg， the AUC ratio and c max ratio of Clo-AM were 0.75 and 0.63， respectively. When the dose of STS was increased to 80 mg， the AUC ratio and c max ratio of Clo-AM were 0.62 and 0.56， respectively. Sensitivity analysis indicated that the absolute values of normalized sensitivity coefficients for the lipophilicity of Clo-AM， the inhibition constants of STS for CYP2C19 and CYP3A4， and the hepatic clearance of Clo-AM were 15.19， 11.34， 10.98， 3.08， respectively. These parameters were the highly sensitive parameters in the DDI between STS and Clo during co-administration. CONCLUSIONS The established PBPK model can be used to predict the DDI between STS and Clo during co-administration. Co-administration of STS and Clo may lead to decreased exposure of Clo-AM. The lipophilicity-related parameters of Clo-AM and the inhibition parameters related to CYP3A4 and CYP2C19 are key parameters influencing the prediction of Clo-AM exposure， among which the inhibitory effects of STS on CYP3A4 and CYP2C19 may be an important mechanism mediating the DDI between STS and Clo.
