Integrated TK-TD Model Evaluation Of Radix Aconiti Kusnezoffii And Compatibility Of Mongolian Medicine Terminalia

Objective: An integrated TK-TD model with indirect response to toxicity was established using the ADAPT 5 program as a new quantitative framework to assess abnormal heart rate and QT interval changes caused by Radix Aconiti kusnezoffii(RAK).Furthermore,the established TK-TD model was applied to the fitting of the1:1 ? 1:3 and 3:1 compatibility of Mongolian medicine Terminalia to explore the possible mechanism.Method:(1)The Ulti Mate 3000 series high performance liquid chromatograph and Q Exactive quadrupole-electrostatic field orbit trap high resolution mass spectrometry detection system.Standard with ultrapure water dissolves,with mobile phase of acetonitrile: water(0.1% formic acid)=35:65,as mobile phase,Hypersil Gold chromatographic column separation,through the selection of high resolution mass spectrometry(Full scan/ion monitoring(Full MS/SIM)model for screening qualitative and quantitative detection.(2)TK-TD model study in rats after intragastric administration:(1)Male SD rats were randomly divided into blank group and low grass(0.36g/kg),medium(0.42g/kg),high In the(0.49 g/kg)dose group,blood was taken from the carotid arteries at 0.5,1,1.5,2,3,5,7,10,12 and 24 h after a single intragastric administration.Heart rate(HR)and QT interval indicators were recorded at the same time.Plasma drug concentrations(observations)were determined using UPLC/Q Exactive MS technology.(2)Toxic kinetic model was established: the relationship between time t and observation value was plotted,and the four alternative TK models were tested by maximum likelihood method(ML)under ADAPT 5 program.The AIC and BIC are used to select the best fitting method and model,and then the data is converged and expanded by the Maltab2011 b program.(3)Toxic effect kinetic model was established: time t was established with HR and QT respectively.The time to reach Emax of three alkaloids(t?1.5~2h)was significantly delayed from Cmax(t?1h),and the indirect toxic effect response model of blood concentration-dependent was established.The rate of change of blood concentration-time-toxicity is linked by the Hill's equation.(4)TK-TD integration model establishment: Establish TK-TD structural model and hypothesis H0: ? = S,using Amos 24.0 for correlation analysis and model checking.(3)After the combination of Mongolian medicine Terminalia with RAK in accordance with1:1?1:3 and 3:1 ratio,ADAPT 5 was used to simulate the TK-TD model.Results:(1)Aconitine,Mesaconitine and Hypaconitine in 1-64 ng/m L concentration range inside sex is good,the minimum quantitative limit of Aconitine and Mesaconitine is 0.520ng/m L,and Hypaconitine is 0.204 ng/m L;The absolute matrix effect is between-1.6403~2.131%;Three kinds of diester Aconitine standard addition recovery rate is97.22%~98.73%;precision RSD% is between 0.0971~8.8111%;8 h at room temperature and ?20? refrigerated placed are stability,content determination can not be carried out after 3 times repeated freezing and thawing under-20?.(2)The TK model is a linear first-order elimination kinetic model of the atrioventricular.There is a dose-time dependence of the high-dose raw grass QT interval,so the physiological phase(Biophase)TD model of the indirect toxic effect response model is established for heart rate HR and low-dose QT interval.The Jusko ' s indirect response(IDR)PD model of the indirect toxicant response model was used for the high-dose QT interval,and the TK-TD parameters were output.Model test: Using the ML method,it can be seen that the 0~15 hour fitting values all fall within the maximum and minimum regions.The correctness of the hypothesis model is verified by AMOS analysis.The load factor of the variable is greater than 0.7,the ?2 value is4.169,and the significance level =.041 indicates significant difference.The RMSEA value <0.08 is the best fit.A closer comparison between 0.162 and 0.08 indicates that the model fits well.At the same time,the load factor(correlation coefficient)between HR and QT interval is-0.965,indicating a negative correlation between heart rate and QT.(3)The fitting of TK-TD after compatibility with Terminalia in 1:1,1:3 and3:1ratio showed that the fitting degree of TK model was better than TD,but the overall fit of the model to the in vivo process and effect was lower.Conclusion:(1)This new improved method is suitable for simultaneous determination of Aconitine,Mesaconitine and Hypaconitine.(2)The integrated TK-TD model with one-stage linear first-order elimination kinetics and indirect response is more suitable for explaining the relationship between concentration and cardiotoxicity,and scientifically and accurately predict the cardiotoxicity of rat.(3)Although the TK-TD model of RAK does not predict the TK and TD processes of compatibility with Terminalia in 1:1 ratio,it can be well proved that“Terminalia reduction in toxicity of RAK”leads to changes in TD through the TK process that affects metabolism in the body.It is also suggested that the TK-TD integrated model needs to be further optimized.