Study On Synergistic And Attenuated Of Compatibility Of Rhubarb And Aconite In Yang Deficiency Constipation Model Rats By Methods Of Integrative Pharmacokinetics/Pharmacodynamics

ObjectiveBased on the theory of compatibility of traditional chinese medicine and combined with traditional chinese medicine syndrome yang deficiency constipation,methods of pharmacokinetics and pharmacodynamics were used to explore the material basis and mechanism of the compatibility of rhubarb and aconite in the treatment of yang deficiency constipation.MethodsIn vitro test method to determine the changes of tension,amplitude,frequency of the isolated colon after administration of rhubarb(DH)and compatibility of rhubarb and aconite(DF),comparison of the original drug and drug-containing plasma on the isolated colon of normal and model rats respectively and to explore the material base of rhubarb multiple pathways to play the role of yang deficiency constipation(YDC).After oral administration of DH to the normal and YDC rats,the pharmacokinetic study of aloe-emodin,rhein,emodin and chrysophanol was carried out by HPLC and MTL,GT,ET and VIP were measured by pharmacodynamics at the same time.Comparing the changes of pharmacokinetic parameters of the components the changes of MTL,GT,ET and VIP in normal and model rats,to explore the material basis and mechanism of DH treatment of yang deficiency constipation.After oral administration of DF to the normal and YDC model rats,comparing the changes of pharmacokinetic parameters of the components the changes of MTL,GT,ET and VIP in normal and model rats similarly and further explored the material basis and mechanism of synergistic and attenuated of DF.The pharmacokinetic components of aloe emodin,rhein,emodin,chrysophanol and the pharmacodynamic components of MTL,GT,ET and VIP were calculated by comprehensive calculation of respectively by using the principal component dimensionality reduction method.And using the Win Nonlin 6.30 software,thecomprehensive value of the DH and DF of pharmacokinetic and pharmacodynamic in the normal and model were fitted with the PK-PD model to further analyze the mechanism of DH and DF in the treatment of YDC.ResultsPharmacokinetic results: After oral administration different doses of DH in normal rats,the Cmax and AUC0-? of each component increase with the increase of the dose.The absorption of each component is dose dependent.The degree of absorption was emodin> aloe emodin> rhein> chrysophanol;From the Tmax,emodin absorption of the fastest,the highest absorption of aloe emodin,followed by emodin> rhein>chrysophanol> aloe emodin;from the T1/2,the fastest elimination of emodin,And chrysophanol was the slowest,followed by chrysophanol> rhein> aloe emodin>emodin;After oral administration different doses of DH in YDC rats,the absorption of each component is dose dependent.From the Cmax and AUC0-?,emodin was the best,followed by emodin> aloe emodin> chrysophanol> rhein;from the the Tmax,the emodin was the fastest absorbed,followed by emodin> aloe emodin > chrysophanol>rhein;from the T1/2,emodin to eliminate the fastest,followed by chrysophanol> aloe emodin> emodin> rhein.After oral administration different doses of DF in normal rats,the Cmax and AUC0-? of each component increase with the dose of the administration,and the absorption of each component is dose-dependent.The absorption rate of rhubarb was higher than that of other components,followed by rhubarb> aloe emodin> emodin>chrysophanol.From the Tmax,the absorption rates of low and middle doses were aloe emodin> Rhubarb> emodin> chrysophanol,high dose after administration,the absorption rate of each component was significantly reduced,peak time significantly prolonged;from the T1/2,low and medium doses,the absorption of each component in order to eliminate For the aloe emodin> rhein> chrysophanol> emodin,high dose after administration,in addition to the elimination of emodin accelerated,the remaining components of the elimination rate were significantly reduced.After oral administration different doses of DH in YDC rats,the Cmax and AUC0-?of each component increase with the dose of the administration,and the absorption of the components is dose-dependent.The absorption rate of rhein was significantly higher than that of other components,followed by rhubarb> emodin> aloe-emodin>chrysophanol.From the Tmax,the absorption rates of the components between low and middle dose were chrysophanol> aloe emodin> emodin> rhein,high dose after administration,in addition to emodin and rhein at high doses of the absorption rate was significantly slowed down,peak time was significantly extended;from the T1/2,the removal rate of each component The rate of elimination was decreased,followed by the order of aloe emodin> emodin> chrysophanol> rhein.Pharmacodynamics Results: The contents of MTL,GT,ET and VIP in plasma were significantly lower than those in the normal group;the contents of GT and ET increased significantly after administration of DH,and the contents of GT and ET increased significantly similarly.There was no significant difference in the contents of VIP and MTL between DH and DF.In vitro experimental results: Compared with the normal group,DH had significant excitatory effect on isolated colon rat in tension,frequency and amplitude.DF had the same excitatory effect on isolated colon with DH;Similarly,compared with the YDC group,DH had significant excitatory effect on isolated colon rat in tension,frequency and amplitude,and high dose of DF inhibition of isolated colon contraction,but no significant difference.Integrate PK / PD results: The model is best fitted with a room Sigmoid Emax model with no lag time in the effect room.The EC50 and Emax values of DH were similar to those of normal and YDC rats.The EC50 of DF was significantly lower than that of DH,while the value of Emax was significantly increased.The pharmacokinetic curve of the normal rats was steep,and the pharmacodynamic curve of the model rats were flat.ConclusionsPK/PD results showed that the DF,On the whole,slowing the absorption of anthraquinone,and to avoid the rapid effects of drugs,but also to delay the drug in the elimination rate,prolong the drug retention time in the body to ensure the role of diarrhea lasting.From the absorption and elimination of a certain extent,explained the combination of DF treatment of YDC with synergistic characteristics of attenuated compatibility;From the pharmacokinetic parameters of the constituents,it was speculated that rhein and emodin may be the main material basis for the treatment of yang deficiency constipation and play a therapeutic role by promoting the secretion of GT and ET.The results of integration of PK/PD model showed that the DF could slow down the equilibrium velocity between the effector and the central chamber,and increase the combination of anthraquinone and the receptor at the same time.While promoting the efficacy of components and target site of the receptor,in enhancing the role of rhubarb diarrhea while reducing toxicity.The integrated PK/PD model provides new ideas and methods for the study the Synergistic and Attenuated of compatibility of Rhubarb and Aconite.