The Pharmacokinetics Study Of Flunixin Meglumine Oil Suspension In Dogs And Swine

Flunixin meglumine(FM)is the only animal exclusive non-steroidal anti-inflammatory drug.It can alleviate fever,analgesia and anti-inflammation by inhibiting cyclooxygenase,blocking arachidonic acid to produce prostaglandin(PG)and thromboxane(TX).In veterinary clinic,FM injection has been widely used to relieve fever,inflammatory diseases,muscle and soft tissue pain,such as horses,cattle,sheep,swine and dogs.However,the half-life of ordinary injection is short and the irritation of administration is great.It is urgent to develop a new drug-loading form with long duration and minor irritation of administration.Based on this,we tried to prepare FM oil suspension.In this paper,we studied the release of FM oil suspension behavior in dogs and swine.First,an ultra performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)method was developed for determination of Flunixin(FLU)in dogs and swine plasma.The pharmacokinetics of two different formulations of FM oil suspensions in dogs and swine was studied,and its feasibility and comparative advantage as a new drug delivery form were evaluated.1 Establishment of an UPLC-MS/MS method for determination of flunixin in dogs and swine plasmaAcetonitrile was used to extract the tested substances in dogs and swine plasma.The extraction solution was dried with nitrogen,redissolved in mobile phase solution,and gradient eluted by Acquity UPLC BEH C18 column.In the electrospray ionization(ESI+)mode,multiple reaction monitoring(MRM)mode was selected for analysis and internal standard method was used for quantitative analysis.The matrix effect in dogs and swine plasma was slight(85%≤ME ≤115%),and FLU was linear in the concentration range of 1～500 ng·mL-1(R2>0.999).The limit of detection(LOD)and the limit of quantification(LOQ)were 0.5 ng·mL-1 and 1 ng·mL-1,respectively.In dogs plasma,the recovery rate was 92.16%～113.89%,the precision of intra-and inter-day was 1.36%～7.30%.In swine plasma,the recovery rate was 95.61%～103.69%,and the precision of intra-and inter-day was 0.29%～2.96%.The results showed that the method is specific,sensitive,accurate and reproducible,and it was suitable for the determination of FLU concentration in plasma of dogs and swine.2 Pharmacokinetics study of flunixin meglumine oil suspension in dogsTwelve healthy beagle dogs(10±2 kg)were randomly divided into two groups.The first group was injected with 3 mg.kg-1 b.w.FM oil suspension Ⅱ intramuscularly and the second group was injected with 3 mg.kg-1 b.w.FM oil suspension Ⅱ intramuscularly.Blood samples were collected from cephalic veins at 0.25,0.5,0.75,1,2,3,4,6,8,12,24,30,36,48,54,60,72,78,84 h and 96 h post administration,respectively.The plasma samples were extracted by acetonitrile,concentrated by nitrogen blowing,redissolved by 30%acetonitrile water solution and filtered.The blood concentration was detected by UPLC-MS/MS.And the pharmacokinetics parameters were analyzed by WinNonlin software non-compartment model.The first group parameters were as followed:the mean elimination half-life(T1/2λ)was(15.96±7.16)h,the peak concentration was(Cmax)was(6979.19±1457.93)ng·mL-1,the peak time(Tmax)was(1.33±0.52)h,the mean area under the concentration time curve(AUC0→t)was(38390.67±13046.23)h·ng·mL-1,the mean retention time(MRT0→t)was(10.84±6.32)h.The second group parameters were as followed:T1/2λ was(11.36±1.68)h,Cmax was(6311.80±2410.06)ng·mL-1,Tmax was(1.00±0.00)h,AUC0→t was(23295.43±5539.74)h·ng·mL-1,and MRT0→t was(7.73±3.19)h.In conclusion,the half-life of FM oil suspension Ⅰ and FM oil suspension Ⅱ in dogs were longer than that of FM common injection,and FM oil suspension Ⅰhas longer half-life and better absorption effect than FM oil suspension Ⅱ.3 Pharmacokinetics study of flunixin meglumine oil suspension in swineSix healthy binary crossbred swine(15±2 kg)were intramuscularly injected with 5 mg·kg-1 bw FM oil suspension I.Blood samples were collected from the anterior vena cava at 0.33,0.66,1,2,3,4,6,8,10,12,14,16,24,30,36,48,54,60,72,78,84,96,102 h and 108 h post administration,respectively.The plasma samples were extracted by acetonitrile,concentrated by nitrogen blowing,redissolved by 30%acetonitrile water solution and filtered.The blood concentration was measured by UPLC-MS/MS.The pharmacokinetics parameters were analyzed by WinNonlin software non-compartment model.The pharmacokinetics parameters were as followed:T1/2λ was(7.90±1.01)h,Cmax was(2686.83±680.89)ng·mL-1,Tmax was(0.94±0.61)h,AUC0→t was(20323.14±5886.21)h·ng·mL-1,MRT0→t was(9.56±1.07)h.The half-life of FM oil suspension Ⅲ was longer than that of FM injection and it had better sustained-release effect in swine.