| Antofloxacin hydrochloride is a new fluoroquinolone antibiotics belong to the first type of new drug in China, which is safe and broad spectrum. Pharmacokinetic studies of antofloxacin hydrochloride on mice, rats, Chinese healthy male volunteers, rabbits have been reported in the literature. The purpose of the present study is to broad the clinical use and provide theoretical basis for fair use of antofloxacin hydrochloride tablets in pets by evaluating the pharmacokinetic and pharmacodynamic characteristics of antofloxacin hydrochloride in dogs.The purpose of this experiment is to study the pharmacokinetic and pharmacodynamic characteristics of antofloxacin against clinical isolated salmonella in dogs, in order to design a reasonable dosage regimen for treatment of salmonella infection for dogs. 1. In vitro pharmacodynamic study of antofloxacin against clinical isolated salmonella.Determine MIC, MBC and MPC, MSW of antofloxacin against clinical isolated salmonella by broth dilution method and agar plate method, respectively. Bactericidal test is performed in different concentration of antofloxacin in MH broth. PAE is determined by drug removal method.Results: The MIC and MBC is 0.5μg/m L and 1.0μg/m L, respectively. MPC is 1.6μg/m L, and MSW range from 0.5μg/m L to 1.6μg/m L. The PAE is 11.08 h after exposed to a concentration of 2 times MIC MH broth for 1 hour.Conclusion: In vitro, antofloxacin shows a good antibacterial capability gainst clinical isolated salmonella, concentration-dependent bactericidal mode and a long PAE. 2. HPLC method for determination of antofloxacin in dog plasma.Establish a validated HPLC method for determination of antofloxacin in dog plasma by choosing proper sample treatment method, adapting suitable detector and optimizing chromatograph conditions.Results: Serum samples were deproteinized by the addition of 10% trichloroacetic acid, 40μL supernatant was aspirated for HPLC assay, the mobile phase was composed of 84:16:0.4(v/v/v)potassium dihydrogen phosphate solution(p H 3.0, 50 m M)-acetonitrile- triethylamine. The effluent rate was 1.5 m L/min. A UV detector was employed for monitoring antofloxacin at a wavelength of 297 nm. The calibration curve was shown to be linear between concentrations of 0.1 and 10mg/L(r=0.9998). The regression equation was Y=31737X+3433.3, average absolute recovery was 69.75%.Conclusion: The method is sensitivity, accuracy and repeatability, recovery meets the requirements for analysis of biological samples, and can be adapted in the pharmacokinetics study of antofloxacin hydrochloride tablets in dogs. 3. Pharmacokinetic study of antofloxacin hydrochloride tablets, after single oral dose administration in dogs.Twelve dogs for experiment were divided into two groups random Ly, take a single oral dose administration of 10 mg antofloxacin per kg body weight. Model simulation and parameter calculation was performed by pharmacokinetic software.Results: After single oral dose administration of antofloxacin hydrochloride tablets in dogs, the pharmacokinetic characteristic conforms to 2-compartment model with 1st order absorption and lag time.The main pharmacokinetic parameters of healthy dogs are t1/2α= 1.794±0.837 h,t1/2β= 7.937±1.126 h, T(peak) = 2.300±0.788 h,C(max) =2.672±0.198μg/m L,AUC= 27.282±0.850μg/m L*h,V/f(c)= 2.311±0.136(mg/m L)/(μg/m L),CL(s)= 0.366±0.012mg/m L/h/(μg/m L),the fitting equation is C= 1.1364e-1.095t-14.5606e-0.479t+13.4240e-0.088 t. For the infections, the parameters are t1/2α= 1.766±0.534 h,t1/2β= 8.071±2.295 h,T(peak) =1.430±0.901 h,C(max) =4.353±0.838μg/m L,AUC= 27.571±4.833μg/m L*h, V/f(c)= 1.397±0.187(mg/m L)/(μg/m L),CL(s)= 0.371±0.069mg/m L/h/(μg/m L),the fitting equation is C=-9.0948e-1.546t+8.0775e-0.414t+1.0172e-0.091t。Conclusion: Following single oral dose administration, antofloxacin demonstrated rapid absorption, broadbody distribution, high serum concentration, and a long elimination half-life, about 8 hours. In infected dogs, body distribution is very significant narrower than normal, and serum peak concentration is significant high. 4. Construction of PK-PD model and defination of dosage regimen.Choosing AUC0-24/MIC as model fitting parameter, Win Nonlin software(5.2.1) was used for model simulation, the PK-PD model was Sigmoid Emax.Connected with the administration equation: X=d ×(AUCex vivo/MICtested)/ AUCin vivo/MICtarget, we could define the reasonable dosage regimen for treatment of salmonella infection in dogs.Results: PK-PD model equation is E= 3.580- 9.07C1.17/( C1.17+25.251.17). As dog Salmonella infection(MIC 0.5μg/m L), for prevention, the dosage is 3.47 mg/kg/d; Therapeutic dosage is 10.35 mg/kg/d body weight administered, for eradication of bacteria and to avoid bacteria resistantance, the dosage is 17.28 mg/kg/d body weight administered.Conclusion: For salmonella infection treatment of dogs, the dosage of 17.28 mg/kg/d body weight oral administered once a day can kill the bacteria and avoid bacteria resistantance. Therapeutic dosage is 10.35 mg/kg/d body weight oral administered once a day, and for prevention, the dosage is 3.47 mg/kg/d once a day. |
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