Effect Of Alpinia Officinarum Extract On The Pharmacokinetics Of Indomethacin In Rats

Objective:With the increase of combined application of Chinese herbal medicine and prescription drugs in clinical practice,the study of drug interaction becomes very essential and has more important clinical significance.The aim of this study was to investigate the effects of Alpinia officinarum on the pharmacokinetics of indomethacin in rat,in order to provide guidance for its clinical application.Methods:An accurate and sensitive UPLC-MS/MS method was established and validated for the determination of indomethacin and its metabolites in rat plasma,liver and kidney tissues,bile,feces and urine.The concentrations of indomethacin and related metabolites in different biological samples were determined by validated analysis method after extraction by protein precipitation method,and pharmacokinetic parameters were calculated by DAS software.Results:1、Effect of Alpinia officinarum Extract on plasma pharmacokinetics of indomethacin and its metabolitesThe maximum plasma concentration of indomethacin was 56.50μg/mL after intragastric administration alone,and the maximum plasma concentration decreased to 37.40μg/mL after single administration of A.officinarum ethanolic extract（S-AOE）and to 34.80μg/mL after repeated administration（M-AOE）.Plasma concentration-time curve(AUC_0–t)of indomethacin decreased from 731.95μg/mL·h to 543.17μg/mL·h and 463.68μg/mL·h,respectively.The retention time（MRT）of indomethacin decreased and the clearance rate（CL）increased significantly at the same time.The parameters of the metabolite ODI were all cut down in M-AOE group,but no statistical difference.There was no significant difference in the PK parameters of NDI among all groups.2、Effect of A.officinarum on distribution of liver and kidney tissue of indomethacinThe C_-max and AUC_0–t of indomethacin were 1772.50μg·L-1 and 3382.5μg/L*h in liver tissue after single oral administration of indomethacin.While the C-_max of indomethacin increased to 2622.5μg·L^-1and AUC_0-t increased to 9820.13μg/L*h after oral administration of A.officinarum ethanol extract before receiving indomethacin.Moreover,compared with the single oral administration of indomethacin group,the AUC_0–t and C_-max of IDAβG metabolites were significantly decreased after oral administration of A.officinarum ethanol extract before receiving indomethacin.In addition,the distribution of indomethacin and its metabolites ODI and NDI in renal tissues decreased significantly after combined administration,except for IDAβG.3、Effect of A.officinarum on excretion characteristics of indomethacin administration ratsThe UFLC-MS/MS method was determined indomethacin and its metabolites after oral administration of indomethacin solution with and without the ethanol extract of A.officinarum in rat bile,urine and feces.The results show that the cumulative excretion of indomethacin was 7.53%,IDAβG was 75.86%in indomethacin model group within 7h.The cumulative excretion of indomethacin was14.52%,IDAβG was 52.82%after oral administration of A.officinarum ethanol extract before receiving indomethacin.However,the urinary cumulative excretions of indomethacin and its metabolites in both experimental groups were very little（<2.5%）,and the fecal cumulative excretion rate was less than 4.1%at 28h.Suggesting that parent drug indomethacin was mainly metabolized to the phaseⅡmetabolites of IDAβG in liver and excreted in the bile.Conclusions:Our results first clarified that combined administration of A.officinarum ethanol extract before receiving indomethacin can significantly reduce the systemic exposure of indomethacin and decrease retention time in plasma,and improve the indomethacin clearance rate through bile and feces.The results of pharmacokinetic study on the combination of A.Officinarum and indomethacin suggest that the combination of Chinese and western medicine should be cautious in the clinical treatment of diseases.Before the clinical use of Chinese and Western medicine in the treatment of diseases,it should be based on the study of pharmacokinetics of the body,in order to ensure the rationality and safety of the clinical use of Chinese and Western medicine.