Study On The Pharmacokinetics Of TAP And The Establishment Of Physiologically Based Pharmacokinetic In Cyprinus Carpio

Thiamphenicol is a broad-spectrum antibiotic with chloramphenicol.It has a strong inhibitory effect on Gram-negative bacteria,and has a very significant effect on the prevention and treatment of aquatic animals in aquaculture.In recent years,with the gradual deepening of TAP research,it is found that the problem of drug residues in aquatic products and environment not only threatens the health of consumers,but also restricts the development of aquatic products industry.Therefore,it is of great significance and necessity to study the pharmacokinetics of TAP in carp and to explore the establishment of physiological pharmacokinetics.At the temperature of 26±1℃,the carp was administered by oral administration according to the dose of 100mg/kg.The metabolites of TAP in carp were studied by liquid chromatography and ion trap mass spectrometry.Metabolite analysis of possible isomerization products,including deethylase products,hydrogenation products and its isomers,hydroxylated products and its isomers and adding oxygen product and its isomers,according to the parent ion and ion mass to charge m/s in multistage mass spectra ion current and target compounds in extract ion chromatogram comparison and screening.The results showed that no target compounds were found,so TAP was metabolized in the form of the prototypes in the carp.In the material balance experiment,the individual carp and the aquaculture water in the bucket are a closed system,and the balance equation is established according to the material intake,the output and the conservation of material.The carp and water samples were taken respectively after 1,2,4,6 and 8 days of the dosage of 100mg/kg.The final results showed that the total TAP residues in carp and water accounted for the total ratio of 90.5%⁹4.5%.So after deducting the error,TAP basically reached the material balance in the carp body.According to the research conclusions of metabolites,it can be concluded that TAP exists in the form of its original form in carp.Using high performance liquid chromatography tandem mass spectrometry（HPLC-MS/MS）was studied using 30 mg/（kg·BW）single dose oral administration of TAP after feeding on carp（Thiamphenicol,TAP）on the pharmacokinetics of carp.The drug-time data of TAP in the carp were analyzed by the DAS2.0 dynamic software,and the experimental results showed that the two compartment model was in line with the first order absorption.TAP in different tissues of muscle,liver,kidney,skin,gill,spleen and plasma drug peak time(T_peak)was 16,2,16,8,0,2 and 16 hours,the peak concentration(C_max)were 15.6,35.3,12.4,9,33,11.6 mg/kg and21.0mg/L;the area under concentration time curve（AUC）were 1084.5,1578.1,777.3,541.1,0.1,478.1mg/（kg·H）and 485.1 mg/（L·H）,the elimination half-life(t_1/2)were 11.4,100.2,54.2,41.1,69.5,38 and 71.9hours.The distribution and elimination rate of TAP in different tissues of carp is quite different.The peak time of kidney peak is shorter and the peak concentration is higher than other tissues.Its elimination half-life is also significantly higher than other tissues.It is presumed that the main organ of TAP accumulation and metabolism in carp.According to the Ministry of agriculture"in animal food"maximum residue limits of veterinary drugs documented TAP in aquatic animal MRL（MRL）shall not be higher than50 g/kg,the muscle,liver,kidney,skin,spleen and plasma TAP residue respectively from sixteenth,sixteenth,twelfth,12,lower than 12,10 and 12days MRL,the muscle and kidney tissue TAP as the target of drug residues,recommended the withdrawal period shall not be less than 16 days.At the temperature of 22±1℃and 27±1℃,in 30 mg/（kg·BW）dose of carp for five days feeding bait delivery times.The metabolic trends of the two water temperatures are basically similar.The peak value of the drug was reached in 24h,and the change gradually decreased with time.Under the temperature of different aquaculture water,TAP was absorbed rapidly and widely in the tissues of carp,and the tissue penetrability was strong.The drug taking period is determined by the slow metabolic tissue as a residual target cell.According to the 30 mg/（kg·BW）of the continuous feeding dose administration of 5days,the withdrawal period of not less than 20days and 16days respectively.This paper established a TAP based on metabolism and pharmacokinetics study on physiological medicine in carp dynamic model（physiologically based pharmacokinetic model,PBPK）.The model is constructed with the blood,muscle,liver,kidney,skin,gills and spleen of carp.In the sensitivity analysis of the model,renal clearance rate,organ volume parameter,tissue plasma distribution coefficient are the parameters which have great influence on the accuracy of the model.In the model predictive value and measured value of the correlation analysis,through the measured scatter correlation evaluation model of the crude drug and the predicted values of the degree of agreement.The results show that the fitting results were consistent with the experimental data,so the drug model is reliable for predicting drug residues.In summary,based on the research of TAP in the carp in vivo metabolites,pharmacokineticsandestablishedphysiological pharmacokinetic model for the rich aquatic animal in China based drug pharmacokinetic data and carry out drug residues in aquatic products evaluation make the corresponding contribution and provides a scientific basis.