الفهرس 
Chapter I : IntroductionOnly 14 pages are availabe for public view
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Abstract
The pharmacokinetics of norfloxacin was studied on 12 female lactating goats (8 normal and 4 experinmentally Escherichia coli infected goats). Goats were divided into 3 groups each one included 4 goats. The pharmacokinetics and bioavailability norfloxacin were calculated in normal goats after a single intramuscular dose. The drug clearance, urine output and retaining clearance were investigated in normal and experimentally Escherichia coli infected goats following intramuscular administrations of 10 mg norfloxacin /kg.b.wt. once daily for five consecutive days. The in vitro protein binding percent of norfloxacin was determined microbiologically. Following a single intravenous injection of 10 mg norfloxacin /kg.b.wt. in normal goats, norfloxacin could be detected in a therapeutic concentration 24 hours post intravenous dose with value equal to 1.18 µg/ml. the serum concentration-time curve of norfloxacin following intravenous injection showed that the drug obayed a two-compartments open model. This observation indicated that the body was viewed as consisting of two-compartments: a central compartment of plasma and rapid equilibrating tissues, and a deeper slower equilibrating compartment (skin and connective tissues). Norfloxan after intravenous dose revealed a rapid distribution phase (α = 0.29 h-1) with a distribution half-life (t0.5(α) = 2.38 h). The volume of distribution to central compartment (V1c = 333.64 ml/kg), whereas the calculated body distribution by extrapolation [Vd(B)], area [Vd(area)] and steady state [V(dss)] methods were 701.36 , 483.28 and 423.60 ml/kg, respectively. Norfloxacin was transferred from central to peripheral compartment [K12] at slower rate (0.043 h-1) than its passage from peripheral to central compartment [K21 = 0.181 h-1]. Norfloxacin was eliminated after intravenous injection with a half-life [t0.5(β)] of 5.69 hours and cleared by all clearance processes in the body at a rate of 0.184 ml/kg./min.
The mean peak urine concentrations of norfloxacin were reached 1 hour post intravenous injection with a value of 682.5 µg/ml. The ratio between the urine to serum concentrations ranged from 10.34 to 26.30. These ratios showed a high penetration of norfloxacin from blood to urine. The creatinine concentrations in serum and urine were ranged from 1.37 to 1.89 and from 138.01 to 159.52 mg/100 ml respectively. Creatinine clearance from blood of goats showed average rate values ranged from 18 to 19.26 ml/min./10 kg.b.wt. The rate of norfloxacin clearance from blood of goats was gradually increased till reached 5.6 ± 0.14 ml/min./10 kg.b.wt. 4 hours post injection and then gradually decreased till 12 hours. The ratio between norfloxacin clearance and creatinine clearance gradually increased from 0.12 to 0.31 over 2 hours post – intravenous injection and this values indicated that glomerular filteration was the main pathway of norfloxacin elimination through the kidneys of goats with a significant amount reabsorbed back to the blood.
The highest concentration of norfloxacin in milk was recorded 2 hours post intravenous dose with mean value of 9.55 µg/ml. The calculated milk/serum concentration ratio following a single intravenous injection increased from 0.5 to 24 hours. These values showed a high penetration of norflxacin from blood to milk.
Following a single intramuscular injection of 10 mg norfloxacin /kg.b.wt. in normal goats, the drug reached its maximum serum concentrations after 4 hours of injection with value equal to 11.73 µg/ml. Norfloxacin could be detected in a therapeutic concentration 24 hours post intramuscular dose with value equal to 0.92 µg/ml. The absorption half life [t0.5(ab)] was 1.61 hours, apparent elimination half-life t0.5(β) was 4.89 hours and norfloxacin was cleared by all clearance processes (Cltot) with rate equal to 1.29 ml/kg/min.
The mean peak urine concentrations of norfloxacin was reached 2 hours post injection in normal goats (96.81 µg/ml). The ratio between the urine to serum concentrations ranged from 6.36 to 23.70. These ratios showed a high penetration of norfloxacin from blood to urine. The creatinine concentrations in serum and urine were ranged from 1.38 to 1.82 and from 139.54 to 152.81 mg/100 ml, respectively. Creatinine clearance from blood of goats showed average rate values ranged from 14.33 to 18.64 ml/min./10 kg.b.wt. The rate of norfloxacin clearance from blood of goats was gradually increased till reached 3.08 ml/min./10 kg.b.wt. 2 hours post injection and then gradually decreased till 8 hours. The ratio between norfloxacin clearance and creatinine clearance was ranged from 0.07 to 0.13 ml/min./10 kg. b.wt. and these values indicated that glomerular filteration was the main pathway of norfloxacin elimination through the kidneys of goats with a significant amount reabsorbed back to the blood.
The highest concentration of norfloxacin in milk was recorded 4 hours post intramuscular dose with mean value of 9.78 µg/ml. The calculated milk/serum concentration ratio following a single intramuscular injection. increased from 0.5 to 24 hours. These values showed a high penetration of norflxacin from blood to milk.
The mean systemic bioavailability of norfloxacin following a single intramuscular injection in normal goats was 70.04 %; this value referred a better absorption of norfloxacin from its site of intramuscular administration.
The serum concentrations of norfloxacin in normal and experimentally Escherichia coli infected goats following repeated intramuscular injections of 10 mg/kg. b.wt. once daily for five consecutive days, peaked 4 hours after each intramuscular dose with a lower significant values recorded in experimentally Escherichia coli infected goats than in normal goats. This observation might be attributed to the higher penetrating power of the drug to diseased tissues. The absorption half-lives [t0.5(ab)] following a single intramuscular injection of norfloxacin was significantly higher in experimentally Escherichia coli infected goats than in normal goats. The maximum serum concentration (Cmax) were significantly lower in experimentally Escherichia coli infected goats than in normal goats. These concentrations were reached at maximum time (tmax) which were significantly higher in experimentally Escherichia coli infected goats than in normal goats. The elimination half-lives [t0.5(β)] of norfloxacin were significantly higher in experimentally Escherichia coli infected goats than in normal goats. Norfloxacin was cleared by all clearance processes [Cl tot) in the body at a higher significant rates in experimentally Escherichia coli infected goats than in normal goats.
The mean peak urine concentrations of norfloxacin were reached 2 hours after each intramuscular dose with lower significant values in experimentally Escherichia coli infected goats than in normal goats. This observation might be attributed to the higher penetrating power of the drug to the diseased tissues.
Norfloxacin clearance showed lower significant values at variable times in experimentally Escherichia coli infected goats than in normal goats after repeated intramuscular injections.
The ratios between norfloxacin clearances from blood of goats to creatinine clearance decreased with variable significant values at different times in experimentally Escherichia coli infected goats than in normal goats after repeated intramuscular injections. These observations indicated that glomerular filtration seemed to be main pathway of norfloxacin elimination with a limited rate of tubular reabsarption. The urine/serum ratios of norfloxacin showed a high penetration of norfloxacin from blood to urine.
The highest concentrations of norfloxacin in milk reached 4 hours after each intramuscular dose with lower significant values in experimentally Escherichia coli infected goats than in normal goats. This observation might be attributed to accumulation of drug in inflammed tissues. The experimental milk/serum concentration ratios of norfloxacin showed a high penetration of norflxacin from blood to milk. The high penetration of norfloxacin from blood to milk might be attributed to its highest oil water partition co-efficient and considerable low binding to plasma protein.
The in–vitro protein binding of norfloxacin was assayed microbiologically (14.07%). The protein binding percent of norfloxacin was decreased as its concentration increased.
from the present study it could be concluded that, serum concentration of norfloxacin in normal and Escherichia coli infected goats could be detected in a therapeutic level for 24 hours following intravenous and repeated intramuscular administration and exceeded the MIC’S 90% of norfloxacin for most of Gram positive and negative bacteria. The highest concentration of norfloxacin in the urine, suggest that norfloxacin is suitable for treatment of urinary tract infection in goats. The highest milk concentrations of norfloxacin in lactating goats suggested that norfloxacin could be used for treatment of mastitis caused by sensitive organisms in lactating goats as it excreted in milk. The mean systemic bioavailability of norfloxacin following a single intramuscular injection in normal goats was 70.04 %; this value referred a better absorption of norfloxacin from its site of intramuscular administration.