Pharmacokinetic Study Of A Novel Triazine Anticoccidial Drug AC4

Chicken conccidiosis is the major parasite disease of poultry,with substantial economic burden in annual losses. Eimeria tenella and Eimeria necatrix are most harmful of the seven species, they will cause weight loss,decreased resistance and high mortality rate of chicken clinically.AC4 is a novel triazine anticoccidial compound synthesized on the basis of diclazuril by medicinal chemistry laboratory,Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science.Preclinical studies have shown that AC4 is an excellent anti-coccidiosis with broad-spectrum, low toxicity characteristics. The purpose of this study is to establish the detection of AC4 within the plasma of chicken and SD rat,and study the pharmacokinetics of AC4 in chicken and SD rat.In the UPLC-UV method of SD rat:I used ethyl acetate as the extraction solvent,toltrazuril sulphoxide as an internal standard,BEH C18 column with a gradient elution mode,each sample injection was 20 min.Specificity of the method is good, the limits of detection and the limits of quantification were 0.04,0.08 μg/m L respectively;the line arrange of the standard curve was 0.08-80 μg/m L and the regression equation was y=y=0.091x+0.001,R2=1;the extraction recoveries of spiked sample was ranged from 97.56-106.2%,the within-run and between-run precision were less than 6.36 %;the sample was stable after 8 h at room temperature or after repeated freezing and thawing three times.The method is sensitive, accurate, and can be used to detect the content of AC4 in SD rat plasma.In the pharmacokinetic study of AC4 in SD rat,I examined the doses of 0.45,0.9,4.5 mg / kg bw in male and female SD rat,the results showed:there was dose-dependent manner of AUC and Cmax in both male and female SD rat;it was about 4 h reached the peak plasma concentration;There were significant differences of the biological elimination half-life of AC4 between different gender and different doses;obvious gender and individual differences were observed of the pharmacokinetics of AC4 in SD rat.In the UPLC-UV method of Chicken,I used ethyl acetate as the extraction solvent,tolrrazuril sulphoxide as an internal standard,BEH C18 column with a gradient elution mode,each sample injection was 10 min.Specificity of the method is good, the limits of detection and the limits of quantification were 0.02,0.04 μg/m L respectively;the line arrange of the standard curve was 0.04-50 μg/m L and the regression equation was y=0.094x+0.002,R2=0.999;the extraction recoveries of spiked sample was ranged from 92.97-109.5%,the within-run and between-run precision were less than 7.84 %;the sample was stable after 8 h at room temperature or after repeated freezing and thawing three times.The method is sensitive, accurate, and can be used to detect the content of AC4 in chicken plasma.In the pharmacokinetic study of AC4 in chicken,I examined the doses of 0.45,0.9,4.5 mg/kg bw,the results showed:there was dose-dependent manner of AUC and Cmax in chickens;it was about 4 h reached the peak plasma concentration;the average of biological elimination half-life of AC4 is 18.5 h.In the bioavailability experiment of AC4 in chinken,at the dose of 1.33mg/kg bw,AUC(0-t) of oral administration group was 53.836 mg/l*h,AUC(0-t) of intravenous group was 60.068mg/l*h.Bioavailability is calculated according to F = AUCpo / AUCiv × 100%,to give the oral bioavailability of AC4 was 79.1%.In summary,the present study have successfully established the UPLC-UV method for the detection of AC4 in the plasma of chicken and SD rat.I also studied the pharmakinetics of AC4 in chicken and SD rat,and got the major pharmacokinetic parameters.The results of this study,to a certain extent,could be useful to the further research of AC4.