الفهرس 
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Abstract
Sixty three one day old broiler chick of both sexes were used in the present work . Chicken were classified into 5 groups .The 1st and 2nd groups ( 5 normal chicken about 2kgb.wt.; each ), were used to study the pharmacokinetic parameters of ethinylestradiol and norethisterone acetate respectively . The 3rd group ( 5 one day old chick ) was kept as control for assay of biochemical parameters. The 4th and 5th groups (24 one day old chick; each ) were submitted to study the effect of ethinylestradiol and norethisterone acetate on some biochemical parameters, histopathology and residues analysis, respectively .Concentrations and the pharmacokinetics of ethinylestradiol and norethisterone acetate in chickens were investigated following repeated oral administrations for 5 consecutive days . Residues of both hormones in different tissues were also determined .The hepatotoxicity of both tested hormones were investigated biochemically and
histopathologically .
6.1. Ethinylestradiol .
The serum concentrations of ethinylestradiol in normal chickens following repeated oral administrations of 3 lig / Kg b.wt. once daily for 5 consecutive days revealed a high significant increase in serum drug concentrations after the second, third ,fourth and fifth dose when compared to the first doses at all time of sampling . The drug peaked in blood at one hour after each dose and could be detected over 24 hours for 5 days regimen. The absorption half life ( t 0.5 ab ) increased significantly after the second and the third days in comparison to the recorded data in the first day .
The kinetic parameters of ethinylestradiol after repeated oral administration showed decrease in absorption rate constant ( K ab ) after the second and third dose but increased following the fourth and fifth days repeated oral administration .
The elimination half —life (t cop )of ethinylestradiol increased after the third, fourth and fifth day following oral administration ( ranged from 5.76 to 6.17 hours).
The rate of total clearances of ethinylestradiol ( Cl tot ) was
significantly decrease in the second ,third ,fourth and fifth doses in comparison to the first dose.
It was though that discrepancies found in these data were due to differences in animal species ,time of sampling selected to give a basis for interpreting the pharmacokinetic behavior of ethinylestradiol.
Blood and tissue residues of ethinylestradiol in slaughtered chicken following the dosage regimen ( 31.1g /Kg b.wt. once daily from 15th to 45th days old ) showed the high drug residues in liver ,breast muscles and thigh muscles till the 75th days old . the hormone residues were completely cleared after 60 days old in blood ,fat and skin .The contraceptive steroid ethinylestradiol undergoes Enterohepatic recycling .This might explain the high liver concentration of ethinylestradiol .The withdrawal period depends on the way of administration of anabolics, an initial and rapid release of active compound from the site of application ,a decrease in absorption could be observed .This diminished absorption and hence excretion .The formation of hormonal concentrations in tissues , thus seemed to be a problem of a release of compound on one side and the metabolic clearance rate .
The biochemical effects of ethinyestradiol showed highly significant increase in the activities of alanine aminotransferase, aspartate transaminase, alkaline phosphatase at 30th ,45th and 60th days old .Also these results showed significant decrease in total protein ,globulin ratios at 30th ,45th and 60th days old chickens .Albumen showed significant decrease at 30th days old only .
The histopathological examination of the chicken’s liver after repeated oral administrations of 31.tg ethinylestradiol /Kg b.wt. once daily from from l5th till 45th days old revealed congestion of central portal veins and blood sinusoids .Multiple focal areas of lymphocytic cellular aggregation were commonly seen in between hepatic parenchyma particularly at 45 days old. Diffuse perivascular eosinophilic and lymphocytic aggregation were observed . Focal areas of coagulative necrosis of the hepatocytes evidenced by homogenous eosinophilic cytoplasm and pyknosis of the nuclei were also detected in rare cases at 45 days old .The portal area showed lymphocytic cellular infiltration and perivascular fibrous tissue proliferation . Moreover, hyperplasia of the lining epithelium of the bile duct with periductal leucocytic cellular infiltration especially lymphocytes were a prominent lesion at 60 days old .
A useful biochemical index of bile duct damage was a sharp elevation in serum activities of enzymes localized to bile ducts ,particularly alkaline phosphatase .Dilatation of the sinusoid will occur whenever efflux of hepatic blood is impeded .Multiple alterations have been well documented for estrogens ,a well —known cause of reversible canilicular cholestatis .
6.2. Norethisterone acetate .
Repeated oral administrations of 60 pg norethisterone acetate /Kg
b.wt. in chickens once daily for 5 consecutive days revealed a high significant increase in drug concentrations after the second, third ,fourth and fifth doses at all time of sampling when compared to the first dose .Norethisterone acetate was peaked at 4 hours after each dose .The maximum blood level of norethisterone acetate ranged from 48.78 ng /ml at the first dose to 80.24 ng/ml at the fifth dose and attained at 6.12 and 6.29 hours ,respectively .The blood levels of norethisterone acetate could be detected early ( 0.25 hours ) with absorption half lives to.5 ow ranged from 2.49 to 3.37 hours .
The kinetic parameters of norethisterone acetate after repeated oral administration showed significant increase in absorption rate constant
(K ) after the fourth day of oral administration .
Blood and tissue residues of norethisterone acetate in slaughtered chickens following the dosage regemin (60 μg/Kg b.wt. once daily from 15th to 45th days old ) showed the highest hormone residues were detected in liver, breast muscles, and fat till 75th days old .Absence of hormone residues at 6oth days old in thigh muscles and at 45th days old in blood and skin .
The formation of hormonal concentration in tissues due to decrease in absorption and excretion as a results of the decrease of metabolic clearance rate. Tissue residue formation not only depends on the elimination rate , but also on the other factors like mode of application , formula and withdrawal time .
Administration of 60 tig norethisterone acetate /Kg b.wt. once daily from 15th till 45th days old resulted in highly significant increase in the activities of alanine aminotransferase ,aspartate transaminase ,alkaline phosphatase at 30th ,45t1’ and 60th days old. Also these results showed highly significant decrease in total protein ,globulin at 30th ,45th and 60th days old .
Enzyme activities were either decreased or not changed in long period treatments ,it was suggested that increased that increased enzyme activities in short period treatments might increase total cholesterol levels, and that in time, these levels might lead to a suppression of enzyme activities.
The histopathological examinations of the chicken’s liver following repeated oral administrations of 60 lig norethisterone /kg b.wt once daily from 15th till 45th days old showed vacuolar degeneration of hepatocytes represented by presence of small variable sizes intracytoplasmic vacuoles. Multiple focal aggregation of lymphocytes replaced the hepatic parenchyma were seen. Focal areas of coagulative necrosis infiltrated with heterophils and lymphocytes were observed in few cases .The portal areas revealed severe congestion of the portal vein and perivascular fibrosis. Perivascular leucocytic cellular infiltration particularly eosinophils were also detected in the portal area in some cases at 45 days old. Other blood vessels showed endotheliosis . Moreover ,hydropic degeneration of the lining epithelial cells of bile duct and periductal fibrous tissue proliferation infiltrated with lymphocytes were also noticed in the portal area .
There is evidence that indicates a precise structural requirement to induce injury ,namely an alkylgroupC-17, testosterone which lacks this type of substitute ,does not lead to impaired function ,while methyltestosterone with C -17 methyl substitute does.
In the present study both hormones ethinylestradiol and norethisterone acetate induced liver dysfunction represented in histopathological changes which leads to elevation in some liver enzymes and decrease in total protein . Also resulted in residues in breast muscle, thigh muscle , liver , skin and fat tissue. Residues of both breast muscles and livers persist for long time and can be detected till 75 days old . So we can expect possible consumer injury from frequent use of meat from anabolic agent treated animals especially that the European Union has prohibited the use in livestock farming of substances having a hormonal action .
Ethinylestradiol and norethisterone acetate induced liver dysfunction represented in histopathological changes which leads to elevation in some liver enzymes and decrease in total protein . Also resulted in residues in breast muscle, thigh muscle , liver , skin and fat tissue. Residues of both breast muscles and livers persist for long time and can be detected till 75 days old . Possible consumer injury was expected from frequent use of meat from anabolic agent treated animals especially it is illegal to such hormones in animal breeding , there are no permissible limits for ethinylestradiol and norethisterone acetate in meat residues. It is recommended that the usage of these hormones in feeding poultry is prohibited.