| Trimethoprims is a type of dihydrofolate reductase inhibitors,which often associates with sulfa for increasing drugs antibacterial activity,so it was widely used in clinical.Due to these drugs have good antibacterial effects,abuse phenomenon often occurred in the process of production,which affected the control effecsts of the drug synergy and increased drug resistance,and its study of residue elimination was less,so for this kind of drug was safe and effective use in clinic,it was necessary to establish its residual prediction research.Only rely on made up MRL and WDT,cannot better to forecast off-label drugs residues,which could lead to the veterinary drug residues in animals.If listed animals was checked,not only the workload was big,and unqualified sampling can also caused great economic loss.physiologically-based pharmacokinetic model as a new residual prediction method,which can make up for the inadequacy of existing residual prediction method.This study was carried out by PBPK model research of DVD in pigs,and through compound extrapolated to similar drugs TMP and ADP in pigs and species extrapolated to DVD in chicken and fish.Through these studies,the establishment of residueal prediction method perfected the trimethoprims drugs residue monitoring system,increased the PBPK model application category in the field of veterinary drugs.1.Development of the PBPK model of DVD in pigsPhysiological parameters such as swine cardiac output,tissues and organs volume,can be obtained by literature review,chemical-specific parameters,absorption rate parameter initial value was 0.061 h-1,renal clearance was 0.075 L/h/kg,tissues/plasma partition coefficients was the ratio of the DVD in plasma and tissue of area under the concentration time curve?AUC?,were 0.7,1.31,0.38 and 0.53 in the liver,kidney,muscle and fat,respectively.The liver,bile and intestinal metabolic rate constants were obtained by three points after elimination phase,which values were 0.008 h-1,0.017 h-1 and 0.009h-1,these parameters were as initial values of model operation.According to the pharmacokinetic and residue elimination data of DVD,we can established a blood flow-limited speed PBPK model.First order rate process was adopted to describe metabolism of DVD in the liver.Model contained compartments of the liver,kidney,muscle,fat,plasma and other organizations,the enterohepatic circulation process was included.Using experimental data to optimize compound dynamic parameters,the sensitivity analysis was used to determine which parameters were greater influence on the model,were the absorption rate constant,bioavailability,liver metabolic rate constant,intestinal metabolism rate constant,renal clearance and tissues/plasma partition coefficients,respectively.Sensitivity parameters were as the research objects of Monte carlo simulation,to consider the impacts of the change of the parameters for predicting results,and the experimental data was also included in the results of Monte carlo simulation.At the same time,the model was verified with no fitting data,visual analysis,residual analysis,linear regression analysis and a factor of 2 analysis were used to evaluate the predictive ability,the model can well forecast most of the time points of DVD concentration,showed the success of the model.This study used acslXtreme software?advanced continuous simulation language,acslX,Version 3.0.2.1,Aegis Technologies Group,Inc.,Huntsville,AL,USA?in the form of code,this PBPK model was set up.2.Residue depletion study of TMP in pigsThis study had established the HPLC detection method of TMP in pigs edible tissues of liver,kidney,muscle,fat and plasma,the samples were extracted by ethyl acetate and ammonia,purified with column of MCX,dissolved with 0.5%perchloric acid and methanol?67:33,V/V?,HPLC detection,chromatographic column:Zorbax SB-C18,mobile phase:0.5%perchlorate:methanol=67:33,UV detection wavelength:230 nm,sample quantity:20?L,column temperature:30?.The quantitative limits of this method was 40?g/kg in the tissues and plasma of pigs,the average recovery was above 82%at the concentration of 40?g/kg,80?g/kg and 160?g/kg,and the relative standard deviation was less than 10%in the day,and this method satisfied the requirement of related methodology.20 healthy castrated crossbred?DurocŚLandraceŚlarge white?pigs?weight 28 kg?,were oral gavage with TMP at 6 mg/kg b.w for continuous 7 days,when the last administration time,slaughtered animals for liver,kidney,muscle,fat and plasma at 1,3,5,7 and 14 d.HPLC analysis results showed that the highest drug concentration was693.8?g/kg in the kidney at 1 d.Drug concentrations were higher than the LOQ in all organs when stopped at 3 d and 5 d.Drug contents were less than LOQ in muscle and fat,only detected in the liver,kidney and plasma at 7 d,all tissues and plasma drug residues were undetectable at 14 d.3.PBPK model extrapolationBased on PBPK model of DVD in pigs,compounds extrapolated to similar drug ADP and TMP,species extrapolated to PBPK model of DVD in chicken and fish.Physiological parameters of compound extrapolation were similar to DVD in pigs,compound dynamic initial parameters were obtained by literature searching,no found part was assumed consistent with the optimized compound dynamic parameters of DVD in pigs,pharmacokinetic and residue data was used for model fitting.PBPK model of TMP in pigs can be well fitting for drug concentrations in the liver,kidney,muscle,fat and plasma for continuous 7 d,but the predicted value was slightly higher than the experimental value in the kidney at the 7 d after the last time to give TMP,it may be too little blood flow in the kidney,but predicted value was within the scope of the experimental value of 2 factor,the model can well monitor drug residue of TMP in pigs.PBPK model of ADP in pigs also can be well predicted the ADP concentrations in the liver,kidney,muscle,fat and plasma,but model was overestimated concentrations at 3 d in the liver and kidney at 3 d and 5 d after the last time to administrate ADP,this may be due to the liver and kidney with a larger organ volume and plasma distribution coefficients.Physiological parameters of species extrapolated to chicken and fish were gotten by literature.Assuming compound dynamic parameters were constant in species,pharmacokinetic and residue depletion data was used for fitting and validating to model.PBPK model of DVD in chicken had differences between predictive and experimental values at some time points,this may be the physiological structures of the chicken are different from mammals,but the model can predicted the trend of residues of DVD in the chicken.PBPK model of DVD in fish can well fitting drug concentrations in the liver and muscle at 1 d,3 d and 7 d,and 14 d in the liver and kidney,but overvalued DVD concentrations at 3 d in the kidney after the last time to give DVD,this may be associated with tissue blood flow in the kidney,but a factor of 2 analysis results showed that the model predicted values were within the 2 times scope of the experimental values,which conform to the evaluation standard of model,also proved the success of model extrapolation.To sum up,this topic was the first established PBPK model to predict the DVD residue in pigs under different dosage regimen,and through compound and species extrapolated to build PBPK model of ADP and TMP in pigs and DVD in chicken,fish.The research results provided a new means of forcasting for residue monitoring and promoting the improvement of trimethoprims in residue monitoring system,which had an important meaning in ensuring the development of animal food safety and aquaculture. |
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