Significant Impact on Prothrombin Time and Systemic Exposure of Aspirin and Clopidogrel by Coadministered Ligustrazine during Dual Antiplatelet Therapy in Rats
Refereed conference paper presented and published in conference proceedings


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AbstractPurpose
Ligustrazine, active component isolated from Ligusticum chuanxiong hort, is widely used in China to treat coronary artery diseases and cerebral ischemic diseases. Considering the highly possibility of co-administration of ligustrazine in Chinese ACS or TIA patients receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, the current study was proposed to investigate their pharmacokinetics and pharmacodynamics interactions in rats.
Methods
To evaluate the pharmacokinetics interactions, a set of forty-eight Sprague-Dawley rats were randomly divided into six groups (G1-G6) to receive vehicle (G1, n=6), DAPT (G2, n=6), DAPT plus low dose (4 mg/kg) of ligustrazine (G3, n=12), DAPT plus high dose(8 mg/kg) of ligustrazine (G4, n=12), low dose (4 mg/kg) of ligustrazine (G5, n=6) or high dose (8 mg/kg) of ligustrazine (G6, n=6).
Rats from G2, G3 and G4 received an oral dose of aspirin+ clopidogrel (8.3 mg/kg+ 30 mg/kg) on day 1 followed by aspirin+clopidogrel (8.3 mg/kg+ 7.75 mg/kg) for the following 13 days in absence and presence of intravenously administered ligustrazine from day 10 to day 14. Rats from G5 and G6 received ligustrazine intravenously from day 10 to day 14. After last dosing on day 14, blood samples were collected through a jugular vein catheter at different time points. Concentrations of ligustrazine (TMP), aspirin (ASA) and its metabolite salicylic acid (SA), and clopidogrel together with its metabolites [clopidogrel carboxylic acid (CLPM) and clopidogrel active metabolite derivative (CAMD)] in obtained rat plasma samples were analyzed by LC/MS/MS.
To evaluate the pharmacodynamics interactions, another set of thirty-six Sprague-Dawley rats were randomly divided into G1-G6(n=6 for each group) and received the same treatment as above. On day 14 after last dosing, 4.5 ml of whole blood were collected followed by centrifugation at 2000 g for 10 min. The obtained plasma samples were used to perform prothrombin time (PT) assay within 2h to record the time required for clot formation after addition of thromboplastin reagent to tested plasma samples.
Results
It was found that co-administration of ligustrazine altered the pharmacokinetics and pharmacodynamics of aspirin-clopidogrel DAPT significantly. Co-administered ligustrazine could increase the AUC0-t and AUC0-∞ of ASA to about six times while reduce the AUC0-t and AUC0-∞ of CLP as well as the Cmax of CAMD by about 75% in rats receiving two-week DAPT with aspirin and clopidogrel. On the other hand, DAPT with aspirin and clopidogrel has no impact on the pharmacokinetics of ligustrazine. In addition, a significant longer PT was noticed in rats receiving ligustazine (G5, G6) and DAPT in absence and presence of ligustrazine (G2, G3, G4) in comparison to that of control (G1). Furthermore, the lower extent of PT increase in the presence of ligustrazine suggested that
co-administered ligustrazine could offset the anticoagulation effect of DAPT.
Conclusion
In the present study, the herb-drug interactions between ligustrazine and aspirin-clopidogrel dual antiplatelet therapy in rats were investigated for the first time. Ligustrazine demonstrated more significant impact on the pharmacokinetics of aspirin and clopidogrel in rats receiving DAPT than DAPT did on ligustrazine. Although offset DAPT anticoagulation effect by co-administered ligustrazine was noticed in rats, such impact in human undergoing DAPT warrants further investigations.
All Author(s) ListChenyu Qian, Xi Luo, Zhong Zuo
Name of Conference2017 AAPS Annual Meeting and Exposition
Start Date of Conference12/11/2017
End Date of Conference15/11/2017
Place of ConferenceSan Diego
Country/Region of ConferenceUnited States of America
Year2017
LanguagesEnglish-United States

Last updated on 2018-02-10 at 12:32