Research On Safety Evaluation And Bioequivalence Of Selamectin In Dogs

To evaluate the safety and obtain the pharmacokinetic characteristics of selamectin in animals which is helpful for clinical use, acute toxicity test, irritation test, sensitivity test and bioequivalence were conducted in this thesis.Acute toxicity test of selamectin raw materials and preparations were conducted with Karber method following oral and topical administration in mice and rats. In addition, toxicity and side effects were observed in mice and rats with high dose (10 g·kg^-1) preparations follwing topical administration. Eye irritation test and skin irritation test were performed with Japanese long ear breed rabbits. Sensitivity test was detected in guinea pigs. In equivalence test, pharmacokinetics were studied in German shepherd dogs following a tropical application at a dose of 12 mg·kg^-1. 12 dogs were randomly allocated into two groups, males and females in each group were the same in number, the experiment were done in a two-way cross-over design. The wash-out period was 33 d. Blood samples were collected from the antebrachial vein at different time points and analysed by high performance liquid chromatography with automated solid phase extraction and fluorescence detection, the internal standard was doramectin. The standard curve and mean plasma concentration-time curve were determined by Microsoft EXCEL.Due to on the range of 501～15000 mg·kg^-1, LD50 values for raw materials and preparations calculated in acute toxicity test indicated low toxicity or practical non-toxicity in mice and rats. No toxicity and any side effects were observed in mice and rats follwing topical administration of 10 g·kg^-1 preparations. The results of eye irritation test and skin irritation test were wild. The result of sensitivity test was negative. In bioequivalence study, the linear equation was y=0.0146x+0.0451 with a mean coefficient of determination (R²) of 0.9993, the intra-day CV, inter-day CV and mean recovery were <2.89%, <3.31%, >92.56% respectively, and the detection limit was 0.25 ng·ml^-1. The results of the plasma concentrations were analysed using the computer programme WinNonLin5.2, The results showed that the pharmacokinetics of selamectin in German shepherd dogs conformed with one compartment model, the pharmacokinetic parameters of test formulation and reference formulation were as following: AUC (162.5±27) and (160.3±23) ng·d·ml^-1,CL/F (0.150972±0.095856) and (0.154219±0.07889) ml·kg^-1·d^-1, T_max (3.85±0.44) and (3.98±0.39) d, C_max (14.66±4.09) and (13.21±4.92) ng·ml^-1, t_1/2 (2.37±0.67) and (2.43±0.51) d. The mean relative bioavailability of test preparation vs reference preparation was (101±22)%. The variance analysis showed no significant difference between the test and reference formulation in periods and formulations ( P > 0.05). The 90% confidence interval of AUC and C_max of the test formulation calculated from log-transformed values were 97.78%～102.12% and 86.50%～116.93%.Based on the experiments above, some conclusions were obtained below,Acute toxicity test: Low-toxic or practical non-toxic; Eye irritation test and skin irritation test: Wild;Sensitivity test: Negtive;Test formulation and reference formulation were bioequivalent.