Comparative Pharmacokinetics And Target Animals Safety Of Toltrazuril Thixotropic Suspension In Piglets

Toltrazuril is an animal-specific triazinone anticoccidial drug with high efficiency and broad spectrum against coccidium.Toltrazuril absorbed quickly via oral administration and without teratogenicity,mutagenic effect.Totrazuli thixotropic suspension is a new formulation of totrazuli,wich is designed to treat intestinal diseases such as diarrhea caused by Coccidioides suis and some Eimeria.In this paper,to explore the absorption and metabolism regularity and safety of toltrazuril thixotropic suspension,the pharmacokinetics of toltrazuril thixotropic suspension in piglets and the target animal safety in piglets are studied.The results provide a basis for the rational use of drugs in the clinic.1.Determination of Toltrazuril in Plasma by high performance liquid chromatography(HPLC)Totrazoli in plasma was extracted with perchloric acid and HPLC ultraviolet detector was used to detect the concentration of toltrazuril.The mobile phase is acetonitrile:potassium dihydrogen phosphate buffer(52/48,V/V).The detection wavelength is 240nm,and the flow rate is 1.0 mL/min.The results show that the working liquid of toltrazuril has a good linear relationship in the range of 0.05-50μg/mL(R2≥0.9998).The recovery rate was over 90%at spiked concentration of0.1,5,50μg/mL.The intraday and interday variation coefficients were less than 3%.2.Pharmacokinetic characteristics of toxapril thixotropic suspensionThis study has compared pharmacokinetic of market 5%toltrazuril suspension and 5%toltrazuril thixotropic suspension in weaned piglets.16 weaned piglets are randomly divided into 2 groups.The control group was orally administrated with market 5%toltrazuril suspension,and the test group was given 5%toltrazuril thixotropy suspension.blood samples were obtained at setted time points.plasma were separated and the concentration of totrazol in plasma identified usingHPLC method.The pharmacokinetic parameter was calculated using Winnonlin 5.2 software.After orally administration of a single dose of the market Totrazuli suspension(reference substance),the average elimination half-life(T1/28)was 47.522 h,the peak time(Tmax)and the peak concentration(Cmax)was 17.50 h and 27.565 mg/L.The area under the average drug-time curve(AUC)was 1573.452μg/mL/h,and the average residence time(MRT)was 60.226 h.After orally administration of a single dose of the test product,the toxapril thixotropic suspension had an T1/2β of 46.367 h,and the Tmax and Cmax was 31.50 h and 22.402 mg/L,the AUC was 2285.443μg/mL/h,and the MRT was 78.483 h.Compared with the control,its relative bioavailability(F)was 145.25%.The results of statistical analysis show that(T1/2β)and Cmax of the test article are not significantly different from those of the control group(P>0.05),but the AUC and Tmax,MRT and other parameters were significantly different(P<0.05),and the peak time and mean residence time of the tested products were significantly delayed.Therefore,the toxapril thixotropic suspension is absorbed more completely,and the effective blood drug concentration maintained for a longer period.3.Safety evaluation of toxapril thixotropic suspension on target animalThirty-two 4-day-old duroc piglets were randomly divided into 4 groups(8 in each group).Pigs in each group were orally given a dose of normal saline(blank control),20 mg/kg b.w.(1 times the recommended dose),60 mg/kg b.w.(3 times the recommended dose),and 100 mg/kg b.w.(5 times the recommended dose)three times in succession,with an interval of 2 days respectively.Blood was collected from the pig’s anterior vena cava before drug administration and 24 hours after the last administration.The routine blood test and blood biochemical test were conducted in these samples.Pathological examinations were performed on all pigs 24 hours after the last administration.The results showed that all the animals in the experimental group did not die during the test period,and the clinical observations were normal.No abnormal pathological changes were found in all animals.The values of the hematology and biochemical indicators in the four groups were within normal range.This experiment proved that oral administration of toxapril thixotropy suspension within 100mg/kg(5 times the dose)has no toxic effect on pigs.