Impact of Radix Angelicae Sinensis on pharmacokinetics and pharmacodynamics of aspirin and clopidogrel during dual antiplatelet therapy in Sprague Dawley rats
Refereed conference paper presented and published in conference proceedings


Radix Angelicae Sinensis (Danggui), the dried root of Angelicae Sinensis, is widely used in traditional Chinese medicine for treatment of cardiovascular disease and high blood pressure. Due to the antiplatelet and anticoagulant effects of Danggui, it is unavoidable to co-administrate with aspirin and clopidogrel during dual antiplatelet therapy (DAPT) for integrative medicine practice. However, the risk of related herb-drug interactions is unknown. The present study was proposed aiming to preliminarily investigate the impact of Danggui on pharmacokinetics and pharmacodynamics of clopidogrel and aspirin during DAPT in Sprague Dawley (SD) rats.

Two sets of twenty-four SD rats were randomly divided into four groups, including Blank control group (n = 6), DAPT group (n = 6), DAPT + low dose of Danggui group (n = 6) and DAPT + high dose of Danggui group (n = 6). For DAPT and Danggui treatment groups, the rats received an oral dose of 8.3 mg/kg aspirin + 30 mg/kg clopidogrel on day 1 followed by 8.3 mg/kg aspirin + 7.75 mg/kg clopidogrel for consecutive 13 days in absence and presence of oral administrations of Danggui standardized extract (low dose: 0.62 g/kg; high dose: 1.24 g/kg). To investigate pharmacokinetic impact of Danggui, following first dosing on day 14, blood samples were collected at different time points for concentration determinations of aspirin, clopidogrel and their correspondent metabolites including salicylic acid, clopidogrel carboxylic acid and clopidogrel active metabolite derivative, by our developed LC/MS/MS method. In addition, after last blood sampling, all the rats were sacrificed followed by collecting livers for the preparation rat liver microsomes via differential centrifugation. To further estimate the impact on the activities of aspirin esterase and CYP2C19, incubation of aspirin (probe drug for aspirin esterase) and omeprazole (probe drug for CYP2C19) with prepared liver microsomes were conducted followed by monitoring the amount of salicylic acid formed and omeprazole remained. To investigate the pharmacodynamics impact of Danggui, about 4.5 ml of whole blood was collected from each rat to record its prothrombin time for comparison among different treatment groups.

Danggui demonstrated minimal impact on pharmacokinetics of aspirin and clopidogrel during DAPT due to lack of significant differences found in pharmacokinetic parameters of aspirin, clopidogrel and their related metabolites between DAPT group and DAPT + low dose/high dose of Danggui groups. In comparison to the aspirin esterase and CYP2C19 activity from DAPT group, no significant difference was found in any Danggui treatment groups, whereas significant inhibitions on CYP2C19 activity (p<0.01) were noticed in both Danggui low dose and high dose treatment groups with dose-dependent manner. In addition, all DAPT treatment groups demonstrated significantly longer prothrombin time compared with that of control group (p<0.05). Moreover, co-administered Danggui at either low dose or high dose had no influence on the anticoagulant effect of DAPT with aspirin-clopidogrel in rats.

Although CYP2C19 inhibition by Radix Angelicae Sinensis was noticed, its co-administration during DAPT led to minimal impact on pharmacokinetics of aspirin and anticoagulant effect of DAPT. [Financial support from Health and Medical Research Fund (Reference No. 12131521) from the Food and Health Bureau, Hong Kong SAR]
著者Min Xiao, Chenyu Qian, Xi Luo, Zhong Zuo
會議名稱2017 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition
會議地點San Diego, CA

上次更新時間 2018-02-10 於 12:21