| Objective:To investigate the effect of Diosmin on the pharmacokinetics of glibenclamide in rats and the effects of diosmin on the activity of drug metabolic enzymes,and to reveal the effects of Diosmin on glibenclamide in rats.The mechanism of pharmacokinetics in vivo lays the foundation for the rationality of both clinical applications,and also provides a scientific basis for the interaction of diosmin and other drugs.Methods:The rats were randomly divided into glibenclamide group and glibenclamide with diosmin group.Plasma samples were collected from intraocular iliac veins before and after the sample preparation.After sample preparation,the concentration of glibenclamide in rat plasma was determined by HPLC,the plasma concentration-time curve was plotted,and DAS2.0 was used to calculate the pharmacokinetic parameters.SD rats were randomly divided into control group,L-Diosmin group,N-Diosmin group,H-Diosmin group,inhibitor control group(cimetidine),and inducer control group(phenobarbital),every group was continuously administered for 7 days.The probe drug was injected into the tail vein on the 8th day.The drug-time curve of each probe drug was determined by HPLC to obtain the drug activity.The parameters were studied to observe the pharmacokinetic effects of diosmin on various drugs.Results:(1)Study on the pharmacokinetics of glibenin in rats in vivo Compared with glibenclamide group,the plasma concentration of glibencla-mide in combination group was decreased,Cmax、AUC(0-t)、AUC(0-∞)、t1/2 was significantly decreased(P<0.01),CL was significantly increased(P<0.05).(2)To establish a HPLC method for the simultaneous determination of five kinds of probes of chlorzoxazone,tolbutamide,metoprolol,caffeine and midazolam in rats.The separation of the peaks of each sample was comp-lete.There was a good linear relationship between lobar and tolbutamide in the range of 0.25-20 μg·mL-1(r2=0.997,r2=0.9996),and there was a good linear relationship between caffeine,chlorzoxazone,and midazolam in the range of 0.5-20 μg·mL-1(r2=0.9967,r2=0.9970,r2=0.9986),with low,medium,and high concentrations.The intra-day precision RSD of the 5 probes was less than 20%.The recovery rate was 96.58%-102.53%.(3)Compared with the control group,t1/2、AUC0-t and AUC0-∞ of caffeine,metoprolol and tolbutamide were significantly lower in low,medium,and high dose group,CL was significantly higher,and the difference was statistically significant(P<0.05),which indicates that the metabolism of tolbutamide,caffeine,and metoprolol was significantly increased,suggesting that the activities of CYP2C9,CYP1A2,and CYP2D6 were induced,and the degree of induction was comparable to that of pheno-barbital.However,there was no significant difference in the main pharmacokinetic parameters of chlorzoxazone and midazolam between the low,middle and high dose groups(P>0.05).It shows that diosmin has no effect on the in vivo metabolic activity of CYP2E1 and CYP3A4.Conclusions:(1)The concentration of the five probe drugs can be determined simultaneous-ly by HPLC in this experiment to investigate the effects of diosmin on the activity of various metabolic enzymes.Sample determination is quick and easy,with good sensitivity,accuracy,and precision.It is suitable for simultaneously evaluating the effects of drugs on the activities of five important subtypes,CYP2C9,CYP1A2,CYP2D6,CYP2E1 and CYP3A4.(2)Diosmin promotes the elimination of glibenclamide in rats.The cocktail probe drug method proved that diosmin induced the activity of liver CYP2C6,CYP1A2,and CYP2D6,thus inducing the metabolism of gliben-clamide.The induction strength was comparable to that of pheno barbital.Therefore,diosmin should be avoided in combination with drugs that are metabolized by CYP2C6,CYP1A2,and CYP2D6 metabolizing enzymes.If clinically necessary,the dosage should be adjusted to ensure that the desired therapeutic effect is achieved. |
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