A Study Of The Drug Interaction Between Food And Cannabidiol Based On Pharmacokinetics

Objective:To establish a LC-MS/MS method for the determination of cannabidiol in rat plasma samples,To investigate the effects of dietary intakes with regulatory effects on metabolic enzymes on the pharmacokinetics of cannabidiol（CBD）in rats,and to provide references for clinical application of related preparations of CBD.Methods:（1）Using SD rats as the research object,LC-MS/MS and the established protein precipitation（PPT）method were used to determine the pharmacokinetics of cannabidiol in plasma.（2）Effects of single-dose diet on pharmacokinetics of CBD:SD rats were randomly divided into 6 groups.the juice of soybean,red cabbage,capsicum,ginger or grapefruit were intragastrically administered at 10 mL/kg, respectively.and pure water of equal dose was given to control group.Each group was intragastrically administered with 10 mg/kg of cannabidiol at 2 h,24 h and 48hafter administration of food.Then,blood was collected at different time points and the blood samples were treated with established PPT method and determined by LC-MS/MS.DAS 3.0 software and a non-compartmental model to calculate the pharmacokinetic parameters,and the differences in the pharmacokinetic parameters between the food group and blank group were compared.（3）Effect of soybean and cabbage on the pharmacokinetics of CBD for 7 consecutive days:SD rats were randomly divided into 6 groups..Rats in the soy group of high dose and low dose were given with soybean milk of 1 mg/kg and 0.5 mg/kg,respectively,and the first blank group was administrated with pure water of 2 mL Rats in the cabbage juice group of high dose and low dose were given with cabbage juice of 10 mg/kg and 50mg/kg,respectively,and the second blank group was administrated with pure water of2 mL,continuous gavage for 7 days.24 h after the last gavage,intragastric administration of CBD（10 mg/kg）,blood samples taken at different time points after administration,were treated with the established PPT method,using LC-MS/MS detection analysis.Drug concentration-time data were analyzed by DAS 3.0 software and non-compartmental model to compare the pharmacokinetic parameters between different doses of soybean,cabbage and blank groups,and to evaluate the effects of different foods on CBD.Results:（1）We established and confirmed the method for determining the content of CBD in rat plasma.The method has strong specificity,high sensitivity,good precision and accuracy,high recovery rate and weak matrix effect,which can accurately determine the content of cannabidiol in rat plasma.（2）The effect of pure water（blank group）,soy milk,cabbage juice,chili juice,,ginger juice,grapefruit juice（10 mL/kg）on the pharmacokinetics of CBD,comparison between food group and blank group were as follows:the rats were treated with cannabisdiol after 2 hours of food intake,the C_max,AUC_0-t,and CL of the soybean group were 258.32%,293.66%,and 33.47%of the blank group,respectively,and C_max,AUC0-t and CL of the CBD group were159.06%,179.78%,and 58.78%of the blank group,respectively;C_max,AUC_0-t,and CL of the pepper group were 275.42%,247.86%,and 47.04%of the blank group,respectively;C_max and AUC_0-t of the CBD group of the ginger group,and CL were respectively 198.14%,207.88%,and 55.84%of the blank group,respectively;the C_max,AUC_0-t,and CL of the grapefruit group were 215.03%,219.56%,and 58.97%of the blank group,respectively.The half-life of the above food group was lower than that of the blank group,but the gap is not large.The exposure of CBD at different intervals after ingestion of different foods showed that the exposure of CBD was the highest in the soybean group at 2 h,and the exposure of CBD was the lowest at 24 h.The exposure of CBD in the cabbage group was 24 h.The maximum exposure of CBD was 48 h at the interval.The exposure of CBD was the highest in the pepper group and the ginger group.The exposure of the group was the same as that of the group.The grapefruit group was separated by 2 h.The exposure of CBD was the largest,and the exposure of CBD was significantly decreased at 2 h interval.The exposure of CBD was similar at 24 h and 48 h.The effect of the above food on CBD exposure was more than 48 h..（3）The effect of pure water and different doses of soybean on the pharmacokinetics of CBD（10 mg/kg）for 7 consecutive days.It can be seen from the absorption phase that the C_max and AUC_0-t of the low-dose group of soybeans are blank group.The C_max and AUC_0-t of the high-dose group of soybeans were 93.32%and 123.57%of the blank group,respectively.The T_max of the low-and high-dose groups of soybeans was slightly delayed compared with the blank group;The CL of soybean in low-dose group and high-dose group was 81.44%and 97.01%of the blank group,respectively.The low and high dose groups of soybean decreased compared with the blank group,and the T_1/2 decreased and the low dose group decreased more.The effect of pure water and different doses of cabbage on the pharmacokinetics of CBD（10 mg/kg）for 7 consecutive days.It can be seen from the absorption phase that the C_max and AUC_0-t-t of the low dose group of cabbage are blank group.The C_maxax and AUC_0-t of the high-dose group of cabbage were 75.53%and78.25%,respectively,and the Tmax of the low-and high-dose groups of cabbage was slightly delayed compared with the blank group.The CL of low-dose and high-dose groups in cabbage was 78.69%and 110.29%in the blank group,respectively.The T_1/2was prolonged and the low-dose group was prolonged in the low-dose and high-dose groups.Conclusion:（1）The established LC-MS/MS analysis method,which is proved by methodological method to determine the content of CBD in rat plasma samples;（2）The effect of different foods obtained by oral administration on the pharmacokinetics of oral administration of CBD:rat intake Once a soybean,cabbage,pepper,ginger,grapefruit can cause changes in oral pharmacokinetics,increase drug exposure,reduce drug clearance,and with the extension of food intake and drug delivery intervals,exposure The overall trend showed a downward trend with an effect of more than 48 h.（3）The effect of different doses of soybean and cabbage on the pharmacokinetics of oral administration of CBD in rats for 7 days:the drug exposure in the low dose group was higher than that in the high dose group.The reasons for the pharmacokinetic effects of soybean and cabbage on oral CBD may be multifaceted and need further investigation.Food-drug interactions should be emphasized when clinical use of cannabidiol preparations.