| Altrenogest is a synthetic steroid progesterone,which can regulate estrus cycle of female livestock by inhibiting gonadotropin secretion.Altrenogest is of great significance to batch production and management of gilts.It has been approved for estrous synchronization in sows in the European Union and the United States.European and American countries have taken altrenogest as an essential estrus regulator in modern pig production because of solving the key technology of batch production of sows and oral administration easily.In order to promote the intensive development of China’s pig industry,it is of great significance to develop a generic drug of altrenogest to replace the imported original drug.In this study,the clinical pharmacokinetics,clinical efficacy,target animal safety and residue elimination tests of a new 0.4%altrenogest oral solution were carried out,the effectiveness and safety of its regulation of oestrus in sows were evaluated,and the clinical administration plan and withdrawal period were formulated,which provided a scientific basis for new veterinary drug registration and clinical rational application.1 Pharmacokinetics of altrenogest oral solution in giltsA comparative pharmacokinetic study of a single-dose administration of altrenogest oral solution and an imported preparation in 16 healthy pigs was carried out by using a twotreatment,two-period randomized crossover experimental design.Altrenogest concentration in plasma was determined by HPLC-MS/MS method.The concentration-time data were analyzed with Winnonlin5.2 computer program.The main pharmacokinetic parameters of test drug were as follows:Cmax 227.59±83.35 ng/mL,Tmax 1.16±0.52 h,t1/2 3.63±0.72 h,MRT 5.02±0.79 h,AUC 1060.82±410.74(ng/mL)·h.The main pharmacokinetic parameters of imported preparation were as follows:Cmax 152.83±80.34 ng/mL,Tmax 1.58±0.85 h,t1/23.45±0.63 h,MRT 5.21±0.87 h,AUC 786.09±401.91(ng/mL)·h.The parameter Cmax of altrenogest oral solution was higher than imported preparation,and the other pharmacokinetic parameters(Tmax,t1/2,MRT,AUC)showed no significant difference(P>0.05).Compared with imported preparation,the relative bioavailability of altrenogest oral solution was 134.95%.The results showed that altrenogest oral solution had similar pharmacokinetic characteristics to imported preparation,and altrenogest oral solution has better absorption and bioavailability than imported preparation.2 Clinical efficacy of altrenogest oral solution in regulation in giltsThe clinical efficacy of altrenogest oral solution in regulation of synchronous estrus in gilts was investigated.191 gilts were selected for experimental clinical trial and extended clinical trial.The clinical efficacy was evaluated according to the oestrus and gestation of gilts.In dosimetry test,gilts were divided into altrenogest oral solution groups with the high(25 mg/d),middle(20 mg/d)and low(5 mg/d)dose and blank control group.The average estrus time interval of above four groups were 3.45±0.81 d,3.35±0.66 d.5.21±2.65 d and 11.71±5.39 d.The oestrus rate were 100%(20/20),100%(20/20),95%(19/20)and 70%(7/10)respectively.The average estrus time interval of altrenogest treated groups were significantly shortened compared with control group(P<0.05).Therefore,the recommended dose is 20 mg/d.In expand clinical trial,test drug group and control drug group showed good clinical efficacy of synchronous estrus in gilts,and the average estrus time interval were 3.45±0.81 d and 3.35±0.66 d,respectively.Oestrus rate of test drug group and control drug group were 96.72%(59/61)and 98.33%(59/60),respectively.The results showed that altrenogest oral solution is effective in regulation of synchronous estrus in gilts at the recommended dose of 20 mg/d for 18 days.3 Target ainimal safety test of altrenogest oral solution in giltsThe target ainimal safety of altrenogest oral solution in gilts was evaluated.Twenty-four healthy gilts were randomly divided into three experiment groups and one control group.Altrenogest oral solution was administered at a dosage of 20,60,100 mg once daily for 18 days,respectively.The target animal safety of altrenogest oral solution in gilts was evaluated by comparison of clinical signs,blood routine and serum biochemical indexes and histopathology before and after administration.The results showed that there was no obvious clinic symptom in gilts during the experiment.And the blood routine and biochemical indices in each experiment group were within the normal ranges.Within the oral administration at 5-fold recommended dose(100 mg/d),altrenogest oral solution was safe and had no adverse reactions to blood physiological and biochemical functions and main organs of gilts.The results suggested that altrenogest oral solution was safe and had no adverse reactions to clinical sign,hematological indexes and blood biochemical indexes of gilts following the oral administration of the recommended dose of 20 mg/d.4 Residues elimination of altrenogest oral solution in giltsIn order to establish the drug withdrawal period,twenty gilts were used for altrenogest residue elimination test.Gilts were fed altrenogest orally with clinical recommended dose(20 mg/d)for 18 days.Four gilts were slaughtered after withdrawal times of 6 hours and 1,5,10,18 days,respectively.Muscle,liver,kidney and fat samples were collected for residue studies by HPLC-MS/MS.Withdrawal time was calculated by the software of WT1.4.The results showed that all tissues reached the highest drug concentration at withdrawal times of 6 h.The highest total residue levels were found in liver(240.75 μg/kg),followed by fat,muscle,and kidney(137.30 μg/kg,41.13 μg/kg,40.62μg/kg,respectively).The average residue levels of liver,fat,kidney and muscle declined to 72.93 μg/kg,33.75 μg/kg,19.63μg/kg and 8.95 μg/kg at day 1,respectively.Two gilts were found the residues in liver higher than MRL(2 μg/kg)at day 5,and the levels were 6.59 μg/kg,2.88 μg/kg,respectively.The residue levels of other tissues were below the the limit of quantitation(LOD).The residual amount of altrenogest were below the LOD in all tissue samples at day 10.The results of the residue elimination studies showed that liver was the residual target tissue of altrenogest and the withdrawal time of altrenogest oral solution was recommended for 9 days in gilts. |
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