الفهرس 
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Abstract
In the present work the pharmacokinetic of pefloxacin were studied following intramuscular and intravenous injections. I3ioavailability of pefloxacin was calculated in nonnal goats oiler a single intramuscular dose . The effect of liver microsomal enzyme system induction by rifampin or inhibition by carbon tetrachloride on the pharmacokinetic of pefloxacin was studied .
6. 1. Pharmacokinetic of pefloxacin
After a single intravenous. injection of 75 mg 1 kg b.wt , the drug could be detected therapeutically 24 hours post-injection with a value equal to, 1.82 ug / ml. This value was exceed the minimum inhibitory concentrations of most micro-organisms susciptable to pefloxacin . The serum concentration time curve of pefloxacin following intravenous injection showed that the drug obayed a - one compartment open model . This observation indicated that the body was viewed as consisting of one compartment and first order absorption . Pefloxacin was disappeared from central compartment at rate consfant (kel) equal to 0.127 ± 0.002 h-1 . The apparent volume of distribution (Vd) was equal to 1.9 t 0.11 L / kg . This indicated that the large and effective diffusion of drug extracellularly . Pefloxacin was eliminated alley intravenous injection with half-life [t0.5(0)] equal to 5.44±0.11 211 and cleared by all clearance processess in
the body el(tot) with a value equal to 4.03 nil / kg. / min . The high value - -
of total body clearance of pefloxacin in goats indicates extrarenal elimination routes . Serum concentrations of pefloxacin in normal goats following intramuscular administration of 75 mg / kg b.wt. once daily for five consecutive clays were peaked 2hours post - each dose. Pefloxacin levels at 24 hours exceeded the minimum inhibitory concentrations against most microorganisms susceptible to the drug . This proved that intramuscular injection of 75 mg / kg b.wt. once daily for 5 days is a suitable regimen for treatment of infection caused by pathogens susciptable to pefloxacin . The maximum serum pefloxacin concentrations was attained at maximum time (tmax) equal to 2.86 and 2.67 hours at the 1st and 5th doses respectively . The biological half - lives [t0,5(0)] of pefloxacin following multiple intramuscular dosage regimen were 6.61 and 6.80 fiat lstand 5th doses respectively . This indicated that the drug has a longer elimination half - life . The total body clearance decreased from 5.32 at 1st close to 4.82 ml / kg / min at 5th dose . The observed decrease of total body clearance of pefloxacin following multiple dosage regimen might be resulted from decrease in the rate of non - renal elimination .
The ,urine concentrations of pefloxacin during repeated
intramuscular administration of 75 mg / kg b.wt. were peaked 8hr with values equal to 584.1 and 590.0 ug / ml at 1st and 5th doses respectively . The urinary concentrations of pefloxacin showed that 75 mg / kg b.wl. once daily for five days were sufficient for treatment of urinary tract infections . Creatinine clearance in goats expressing the glomerular filtration rate from blood were ranged from 18.67 to 20.6 ml / min 10 kg b.wt. at the fifth day of intramuscular administration . The ratio between pefloxacin clearance from blood of goats to creatinine clearance indicated that glomerular filtration seemed to be the main pathway of pefloxacin elimination with a limited rate of tubular reabsorption . Pefloxacin clearance / creatinine clearance ratio in goats with alkaline urine refered to a limit reabsorption of drug by renal tubules . Since pefloxacin is acid the renal clearance might be expected to be non - ionic diffusion across the tubular epithelium and so vary according to urinary NI .
The highest concentration of pefloxacin in milk were recorded 6 and 4 hours after intramuscular and intravenous injection . The mechanism of blood - milk passage of pefloxacin could be explained on the basis of the non - ionic passive diffusion . The mean systemic bioavailability of pefloxacin following a single intramuscular injection in normal goats was
28.0%.
6 .2 . Pharmacoldoctic of rifampin
The maximum serum concentrations of rifampin following a single and repeated intramuscular injection of 10 mg / kg b.wt. attained at 4 hours post. each dose . The serum concentrations showed a highly significant increase from the 41k day of administration till the 7th clay indicating that , rifampin had a cummulative effect . The kinetic parameters of rifampin after intramuscular administration of 10 mg / kg b.wt. revealed first order absorption rate constant with k(ab) ranged from 0.25 at (4th dose) to
0.27 lr I at (7111 close) in goats . 6 .3 . Effect of rifampin on pharmacokineties of pefloxacin .
The pharmacokinetic interaction is obvious although of moderate intensity. the senim concentrations of pefloxacin were signigicantly decreased in an order of about 50% during the five days of administration of induction induced by 10 mg rifampin / kg than cocentrations after injection of pefloxacin alone .
The absorption rate constant [Kow] and the absorption half life
lt 0.5(ab)-I ofpelloxacin alone idler intramuscular injection of 75 mg / kg
ti.wt.willt 10 nig rifampin / kg were signficantly decreased and increased respectivly. These findings could be explained an interaction occured at the absorption level . The calculated maximum concentrations of pefloxacin were significantly decreased in a magnitude of about 45% in goats injected pefloxacin and rifampin together . The maximum tim of reaching maximum concentrations of pefloxacin were significantly increased attributed to interaction with rifampin at absorption level . The eliminatin rate constant (kel) of pefloxacin in goats coadministered with rifampin significantly decreased than in goats administered pefloxacin alone but the elimination half life 00.50 and total body clearances ( eltot)
increased significantly. These results were attributed .to marked and significant decrease in the absorption process and the induction of hepatic mixed - function oxidase system (cytochrome p450 IllA isozymes). The mean peak urine concentration were significantly decreased in pefloxacin coadministered with rifampin than pefloxacin alone. This was correlated with the decrease in serum concentration of pefloxacin when coadministered with rifampin as a result of hepatic enzymatic induction by rifampin. The creatinine clearance and the ratio between pefloxacin clearance were also decreased .The milk concentrations of pefloxacin in goats decreased in pefloxacin coadministered with rifampin than those administered pefloxacin alone , but still above the minimum inhibitory concentration of most sensitive micro-organisms to pefloxacin , so
pefloxacin used for treatment of mastitis caused by pathogens sensitive to pefloxacin.
6 . 4 Effect of carbon tetrachloride on the pharmacokineti6 of pefloxacin
The maximum serum concentrations of pefloxacin in goats coadministered the drug with carbon tetrachloride was significantly increased than in those administerd pefloxacin alone . The increase in the serum concentration of pefloxacin in experimentaly induced hepatitis by carbon tetrachloride avareged by about 50 % of the drug concentration when given alone . This resulted from the decrease of the oxidative biotransformation of pefloxacin which induced by carbon tetrachloride.
The absorption rate constants and absorption half life of pefloxacin after repeated intramuscular injection were significantly decreased and increased by about 40% to 50% respectively of value in goats administered pefloxacin alone . The calculated maximum concentrations (Cmax) of
pefloxacin and maximum time (tmax ) as well as the maximum (C’ max) and the minimum (C’mm) serum concentrations at steady state during a
multiple dose regimen were significantly increased in goats in experimentally hepatitis goats than in those administered pefloxacin alone . The total clearance of the drug which represents the sum of all clearance processes in the body was significantly decreased during the five days of administration of pefloxacin with carbon tetrachloride than in goats administered pefloxacin alone . The valuable obtained data must be taken in consideration for treatment of animals with pefloxacin and at same time intoxicated liver or treated with carbon tetrachloride to adjust and reduce the dose of pefloxacin.