Preclinical Safety Evaluationof Ketoprofen Injection And Its Pharmacokinetics In Yellow Cattle

Ketoprofen(K TP),as a kind of anti-inflammatory drug,is approved in animal medicine in foreign countries but has not been approved in C hina yet.This study was carried out to investigate preclinical safety of ketoprofen injection and its pharmacokinetics in yellow cattle after intravenous and intramuscular administration(3 mg/kg.b.w.),and intramuscular bioavailability,in order to provide theoretical basis for application of ketoprofen in veterinary medicine in C hina.Preclinicalsafety evaluation mainly includes four aspects.First,the hemolytic test in vitro was performed to assess lysis and agglutination of red blood cells by adding different concentrations of ketoprofen into rabbit red blood cells in vitro.Secondly,rabbits were administrated ketoprofen(3 mg/kg.b.w.)via intramuscular injection,local stimulation effect and pathological section were observed to assess stimulation effect of ketoprofen on muscle.Furthermore,guinea pigs allergic test was performed by injecting different doses of ketoprofen,and then allergy symptoms were observed and incidence was calculated after motivated at 14 and 21 days.Finally,rat passive skin allergy test was performed.Briefly,rat was administrated different doses of ketoprofen and serum was sampled after 14 days,then other rats were injected sampling serum and were stimulated after 24 hours to determine the size of blue spot on the back subcutaneous.The results showed that ketoprofen did not cause lysis and coagulation of rabbit red blood cell,and only had little stimulation effect on muscle regarded as slight stimulation,no distinct pathological changes were observed.Additionally,both low and high dose of ketoprofen did not cause any allergic symptoms in guinea pigs,and no blue spot on the back subcutaneous was observed in rat passive skin allergy test.These data indicate that ketoprofen is safe to inject into animals.Six healthy yellow cattle were divided into two groups adopting the random two-way cross-over design,and each group was administrated ketoprofen(3 mg/kg.b.w.)via intravenous or intramuscular injection.The blood was sampled at 0,5,10,15,20,30,40,and 50 minutes and 1,1.5,2,3,4,6,8,10,12,14,24,30,36,and 48 hours after administration.The concentrations of ketoprofen in plasma wasdetermined using high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The concentration-time data was analyzed by non-compartmental modelusing Win Nonlin 6.2 software.The main pharmacokinetic parameters of ketoprofen afterintravenous administration was:t1/2? z 4.18±0.40 h,MRT3.40±0.52 h,Vd 387.52±46.49 kg·m L-1,C l B 65.29±14.40 m L·(h·kg)-1,AUC0-?47.70±9.41 h·?g·m L-1.The main pharmacokineticparameters of ketoprofenafter intramuscular administration: tmax 0.58±0.21 h,Cmax 11.36±1.14 ?g·m L-1,t1/2? z 4.26±0.73 h,MRT 3.77±0.24 h,AUC0-?43.33±4.59 h·? g·m L-1,F 93.12±13.34%.The above results indicate that ketoprofen is rapidly absorbed and eliminated in yellow cattle after intramuscular administration with high peak serum concentration and bioavailability.