Study On The Drug Interaction Of Erigeron Injection

Erigeron Injection is a preparation of Chinese materia medica,the extraction of Erigeron breviscapus(Vant.) Hand-Mazz.It contains the compounds of phenolic acid and dicaffeoylquinic acid,and has an extensively application in clinical to use for the treatment of hemiparalysis and other cerebrovascular disease or cardiovascular disease.In the Progress of new drug development,it was important to understand the influence on CYP450,and the drug-drug interactions.Since the use of Erigeron Injection is frequently accompanied by the use of multiple drugs,which may cause adverse effect by drug-drug interactions.Hence it was important to consider of the in vitro and and in vivo effect to CYP450 and the risk for drug interaction for further clinical research.So elucidate whether Erigeron Injection was the substrate or inhibitor of CYP450 was very important.Our studies focused on elucidate the in vitro and in vivo effect of Erigeron Injection to the phenotype of CYP450 in mice and rat and the drug-drug interactions of Erigeron Injection to provide a Principle for clinical rational administration,and evaluate the security and rationality of co-administration of Erigeron Injection with western medicine and traditional Chinese medicine.Meanwhile,also provide a theory evidence for the further development of Erigeron breviscapus(Vant.) Hand-Mazz.1.Effects of the Erigeron Injection on Liver Microsomal Cytochrome P450 System in MiceObjective:To investigate the effects of Erigeron Injection on liver microsomal cytochrome P450 system in Mice.Method:Mice were divided into four groups.One is control group(CG), the second is positive control group and the third and forth groups are dosage groups.The mice of CG were given saline only and the mice of positive control group were given Phenobarbital sodium injection(PBN) at 80mg·kg^-1 by peritoneal injection(i.p.),once daily for seven days. The remaining two groups were i.p.with 10 mg·kg^-1(normal-dosage group,NG) and 30 mg·kg^-1 (high-dosage group,HG) Erigeron Injection,respectively,once daily for two weeks.Then all the liver microsomes of mice were prepared with a procedure using polyethylene glycol(PEG);The concentration of protein in liver microsome was determined by Coomassie brilliant blue staining method.The total content and activities of CYP450 of mice were studied by spectrophotometer. Results:The study showed that the content of CYP450 and protein in liver microsomes of mice were higher than that in control group(P＜0.05,P＜0.01),except Liver indexes(P＞0.05).In terms of the Erigeron injection effect on Erythromycin-N-demethylase,the significance difference was exhibited between the treatment groups and control group(P＜0.01).But aminopyrine-N-demethylase activities were not affected(P＞0.05).Conclusions:The Erigeron Injection had no effect on the liver indexes and the levels of aminopyrine N-demethylase in mice. However,the content of CYP450 and protein,and the levels of erythromycin N-demethylase were affected.The Erigeron injection may be an inhibitive agent to CYP3A.2.Simultaneous evaluation of effect of Erigeron Injection on CYP450 activity in rats by Cocktail probe drugsObjective:To investigate the influence of Erigeron Injection on cytochrome P450 isoforms CYP1A2,CYP2E1,CYP3A4 activity by Cocktail probe drugs in rats.Methods:In the study, probe drugs(theophylline,chlorzoxazone and dapsone)were simultaneously given to rats in the absence or the presence of coadministered Erigeron Injection.The plasma concentrations of the three probe drugs were measured by HPLC and the pharmacokinetic parameters were also estimated to evaluate the inductive or inhibitory effects on CYP1A2,CYP2E1,CYP3A4.The results of HPLC method validation showed that the established methods were suitable for bioanalysis.Rats were randomly divided into two groups,one is clinical equivalent-dose group (EG)and the other is high-dosage group(HG).Erigeron Injection were administered i.p.for fourteen days at a dose of 6.5mg·kg^-1body weight for the clinical equivalent dose group and 19.5mg·kg^-1body weight water were administered in the same way for the high dose group.On the first day(absence of Erigeron Injection)and sixteenth day(presence of Erigeron Injection), probe drugs theophylline,chlorzoxazone and dapsone were administered orally at a dose of 30, 50 and 20mg·kg^-1body weight respectively for both of groups.The blood sample were taken from eyeball at 9,5,30min,1,1.5,2,2.5,4,6,8,10,13 and 24h after administration of three probe drugs.The concentration-time data were fitted by DAS(Drug and Statistics For Windows)Pharmacokinetic Program and the main Pharmacokinetic Parameters were calculated by this Program,The effects of Erigeron Injection on cytochrome P450 isoforms CYP1A2,CYP2E1,CYP3A4 were observed indirectly by comparing the Pharmacokinetic Parameter t_1/2 and AUC.Results:The t_1/2β and AUC_0-th of three probe drugs of EG were:theophylline:2.04,3.0h,112.17,132.4μg·h/L;chlorzoxazone:1.71,1.30h,31.18,56.80μg·h/L;dapsone:7.11,10.69h,85.85,84.17μg·h/L between the absence or the presence of coadministered Erigeron Injection,respectively.The t_1/2β of theophylline and dapsone of two groups had significance difference by Student's t test(P＜0.05);The AUC_0-t of chlorzoxazone had significance difference(P＜0.01);The CL of chlorzoxazone had significance difference(P＜0.01),but the other parameters did not have significance difference(P＞0.05).The t_1/2β and AUC_0-th of three probe drugs of HG were:theophylline:1.61,2.39h,119.92,132.35μg·h/L;chlorzoxazone:1.85,0.93h, 36.42,46.42μg·h/L;dapsone:6.90,10.78h,65.91,99.35μg·h/L between the absence or the presence of coadministered Erigeron Injection,respectively.The t_1/2β of theophylline and dapsone of two groups had significance difference by Student's t test(P＜0.05);The AUC_0-t of dapsone and chlorzoxazone had significance difference(P＜0.05,P＜0.01,respectively);The CL of chlorzoxazone had significance difference(P＜0.05);The Cmax of theophylline had significance difference(P＜0.05),but the other parameters did not have significance difference (P＞0.05).Conclusion:The results suggested that high dose Erigeron Injection once daily for 14 days has little inhibition on the activity of CYP2E1 and CYP3A4,and had no influence on CYP1A2.The clinical equivalent dose was considered have little inhibition on CYP2E1,and had no influence on CYP1A2 and CYP3A4.3.Effects of Erigeron Injection on the Pharmacokinetics of buflomedil hydrochloride in ratsObjective:Study the effect of Erigeron Injection on pharmacokinetics of buflomedil hydrochloride in rats,to provide some useful information for clinical medicate.Methods: The rats were divided into 3 equal groups at random:A,B and C.Rats of group A were administered i.p.,normal saline(NS) from the d1 to 10.On the d11,the rats were supplied with 70mg·kg^-1body weight of buflomedil hydrochloride individually;The rats of group B and C were administered i.p.,6.5mg·kg^-1body weight Erigeron Injection(i.p.) and 19.5mg·kg^-1body weight Erigeron Injection respectively,from the d1 to 10.On the d11,the rats were supplied with 70mg·kg^-1body weight of buflomedil hydrochloride 30min after i.p.Erigeron Injection.Plasma concentrations of three groups were detected by RP-HPLC.The pharmacokinetic parameters were calculated by statistical analysis and compared.A ZORABX SB-C18 column(4.6mm×250 mm,5μm)served as the solid phase;the mobile phase was methanol-5mmol·L^-1 ammonium acetate butter(contain 0.5%glacial acetic acid,pH=3.5);column temperature was 30℃and the flow rate,0.8 mL·min^-1;amount of sample added,25μL,ultraviolet detection wavelength,λ=282 nm.The content of buflomedil was determined with chloramphenicol as the internal standard. Results:The pharmacokinetic parameters of the individual administration group of buflomedil hydrochloride were as follows:AUC_0-8(6.396±2.19)μg·mL^-1·h,t_1/2β(0.816±0.06)h;while the combination administration group B buflomedil hydrochloride were as follows:AUC_0-8 (7.732±2.66)μg·mL^-1·h,t_1/2β(0.913±0.26)h,and the combination administration group C buflomedil hydrochloride were as follows:AUC_0-8(8.787±3.16)μg·mL^-1·h,t_1/2β(0.757±0.05)h. Conclusion:The main pharmacokinetic parameters t_1/2β and AUC_0-8 showed no differences between the three groups(P＞0.05).Multiple-dose of Erigeron Injection administered i.p.did not influence the buflomedil's concentration in rat plasma.