Research On Biopharmaceutic Classification And Pharmacokinetic Characteristics Of Ceftiofur Hydrochloride In Ducks

Biopharmaceuticals classification system(BCS)is a scientific framework which is classified based on the solubilities and permeabilities of drugs.BCS has important significance in various aspects including the development of novel drugs and the application for the waiver of bioequivalence.Ceftiofur is the first 3rd generation cephalosporin-class antibiotic used in veterinary medicine for the clinical treatment of bacterial diseases of livestock and poultry such as cattle,pigs,sheep and chickens.With the feature of long-duration effective plasma concentration and minimized administration frequency,the prolonged-action Ceftiofur injection is well received.Several reports were published about the pharmacokinetics studies of the prolonged-action Ceftiofur injection in kinds of animals including cattle,pigs,geese and chickens.However,there are no reports about the pharmacokinetic studies of the prolonged-action Ceftiofur hydrochloride injection in ducks and no research reports about the BCS classifications of Ceftiofur hydrochloride.In this study,the physiological constant database of duck,which was treated as the research target,was established initially for supporting the BCS classifications of Ceftiofur hydrochloride.After that,the solubilities and permeabilities of Ceftiofur hydrochloride were measured,followed by its BCS classifying.Furthermore,in order to provide guidance for the veterinary clinical dosage regimens and the withdrawal period of prolonged-action Ceftiofur hydrochloride injection,the researches were progressed about the pharmacokinetic characteristics of this drug preparation in duck.Meanwhile,the in vitro-in vivo correlation of Ceftiofur hydrochloride was analysed for providing data supports for biowaivers.Through measuring the heart rate,respiratory rate,body temperature,body weight,as well as the length,weight and content p H value of each gastrointestinal segment of ducks which were 1 ~ 16 weeks old,the physiological constant database of duck was established.The solubility and duck intestine permeability measurements of ceftiofur hydrochloride were performed by using the shake-flask method and Everted Gut Sacs method respectively.According to the BCS classification guidance which was issued by FDA,the BCS class of ceftiofur hydrochloride was judged.The results showed that Ceftiofur hydrochloride was dissolved completely in aqueous solutions with various p H values.Beyond that,Ceftiofur hydrochloride solutions with low,medium and high concentration can be partly absorbed in duck jejunum with an apparent permeability coefficient of less than 10×10-6 cm/s.In consequence,due to the high solubility and low permeability of Ceftiofur hydrochloride,it should belong to the class III drug of BCS.The pharmacokinetic characteristics studies of ceftiofur prolonged-action and general preparations in ducks were performed by using the intramuscular and subcutaneous injection administration routes.The general preparation of Ceftiofur in ducks fitted to the two-compartment model with absorption.The t1/2?,t1/2?,Tpeak,Cmax and AUC of Ceftiofur general preparation on ducks,given by intramuscular injection,were estimated to be 1.209 ± 0.042 h,13.352 ± 0.420 h,0.568 ± 0.036 h,5.278 ± 0.114 ?g/m L and 29.231 ± 0.388 ?g/m L·h respectively.The t1/2?,t1/2?,Tpeak,Cmax and AUC of that preparation through subcutaneous injection were estimated to be 1.571 ± 0.058 h,10.913 ± 0.905 h,0.595 ± 0.006 h,4.636 ± 0.039 ?g/m L and 17.018 ± 0.520 ?g/m L·h individually.Similarly,the prolonged-action preparation of Ceftiofur in ducks fitted to a two-compartment model with absorption as well.The Ceftiofur prolonged-action preparation which intramuscularly injected into ducks had t1/2k?,t1/2? Cmax and AUC values of 0.993 ± 0.034 h,18.726 ± 0.558 h,2.533 ± 0.043 ?g/m L,34.383 ± 0.421 ?g/m L·h separately.The Ceftiofur prolonged-action preparation which subcutaneously injected into ducks had t1/2k?,t1/2?,Cmax and AUC values of 1.256 ± 0.021 h,17.157 ± 1.867 h,1.442 ± 0.010 ?g/m L and 17.113 ± 0.594 ?g/m L·h respectively.The relative biological availabilities of ceftiofur prolonged-action,given by intramuscular and subcutaneous injections,were calculated as 117.628% and 100.606% individually.Comparing with general preparations,the prolonged-action of Ceftiofur was found could be assimilated more slowly and has wider distribution,longer half-life and slower elimination rate.It also can maintain the effective concentration of the medicaments for a longer time.Likewise,prolonged-action of Ceftiofur has higher biological availability and certain long-acting as well as sustained-release effects.Moreover,in vitro and in vivo tests of Ceftiofur hydrochloride has partial correlations.Hopefully,the bioequivalence tests of cephalosporin-class drugs which commonly used for ducks could be replaced by the permeability in vitro tests in the future.