Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long-acting preparation at double the label dosage

Oxytetracycline (OTC) concentration in plasma and tissues, plasma pharmacokinetics, depletion from tissue, and toxicity were studied in 30 healthy calves after IM administration of a long-acting OTC preparation (40 mg/kg of body weight) at double the label dosage (20 mg/kg). Plasma OTC concentration increased rapidly after drug administration, and by 2 hours, mean (+/- SD) values were 7.4 +/- 2.6 micrograms/ml, Peak plasma OTC concentration was 9.6 +/- 2.6 micrograms/ml, and the time to peak plasma concentration was 7.6 +/- 4.0 hours. Plasma OTC concentration decreased slowly for 168 hours (elimination phase) after drug administration, and the elimination half-life was 23.9 hours. Plasma OTC concentration exceeded 3.8 micrograms/ml at 48 hours after drug administration. From 168 to 240 hours after drug administration, plasma OTC concentration decreased at a slower rate than that seen during the elimination phase. This slower phase was termed the depletion phase, and the depletion half-life was 280.7 hours. Tissue OTC concentration was highest in kidneys and liver. Lung OTC concentration exceeded 4.4 micrograms/g of tissue and 2.0 micrograms/g of tissue at 12 and 48 hours after drug administration, respectively. The drug persisted the longest in kidneys and liver. At 42 days after drug administration, 0.1 micrograms of OTC/g of kidney was detected. At 49 days after drug administration, all OTC tissue concentrations were below the detectable limit. Reactions and toxicosis after drug administration were limited to an anaphylaxis-like reaction (n = 1) and injection site swellings (n = 2).     

Effect of probenecid on disposition kinetics of ampicillin in horses.

The effect of an oral dose of probenecid on the disposition kinetics of ampicillin was determined in four horses. An intravenous bolus dose (10 mg/kg) of ampicillin sodium was administered to the horses on two occasions. On the first occasion the antibiotic was administered on its own, and on the second occasion it was administered one hour after an oral dose of 75 mg/kg probenecid. The plasma concentration of probenecid reached a mean (+/- se) maximum concentration (Cmax) of 188-6 +/- 19.3 micrograms/ml after 120.0 +/- 21.2 minutes and concentrations greater than 15 micrograms/ml were present 25 hours after it was administered. The disposition kinetics of ampicillin were altered by the presence of probenecid and as a result the antibiotic had a slower body clearance (ClB; 109.4 +/- 6.71 ml/kg hours compared with 208.9 +/- 26.2 ml/kg hours) a longer elimination half-life (t1/2 beta 1.198 hours compared with 0.701 hours) and consequently a larger area under the plasma concentration versus time curve (AUC 92.3 +/- 5.09 mg/ml hours compared with 35.95 +/- 3.45 mg/ml hours) when compared with animals to which ampicillin was administered alone. The ampicillin concentrations observed suggest that the dosing interval for horses may be increased from between six and eight hours to 12 hours when probenecid is administered in conjunction with the ampicillin.     

Pharmacokinetics of ceftazidime in sheep and its penetration into tissue and peritoneal fluids

Serum, tissue and peritoneal fluid concentrations of ceftazidime were studied in ewes after intravenous, intramuscular and subcutaneous administration at 50 mg kg-1 bodyweight. Tissue and peritoneal cages were implanted in the animals studied. After intravenous bolus administration, the mean serum concentration versus time profile was best described by a two-compartment open model. The distribution rate constant (alpha) was 3.5 +/- 1.1 h-1 and the half-life (t 1/2 alpha) 0.22 +/- 0.09 hour. The elimination rate constant (beta) was 0.43 +/- 0.04 h-1 and half-life (t 1/2 beta) 1.6 +/- 0.2 hours. The area under the curve was 275.7 +/- 84.0 micrograms.ml-1 h. The volume of distribution as steady state was 356.1 +/- 208.0 ml kg-1. The penetration ratio into tissue fluid was 62.6 +/- 15.1 per cent and into peritoneal fluid 61.1 +/- 16.5 per cent. After intramuscular injection, the elimination half-life was 1.7 +/- 0.2 hours, the area under the curve was 228.7 +/- 43.3 micrograms.ml-1 h. and the elimination rate constant was 0.42 +/- 0.05 h-1. The penetration ratio into tissue fluid was 68.5 +/- 37.3 per cent and into peritoneal fluid 73.3 +/- 34.4 per cent. After subcutaneous injection, the elimination half-life was 1.8 +/- 0.5 hours, the area under the curve was 231.8 +/- 65.6 micrograms.ml-1 h. and the elimination constant was 0.41 +/- 0.10 h-1. The penetration ratio into tissue fluid was 47.2 +/- 3.5 per cent and into peritoneal fluid 58.1 +/- 15.6 per cent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory tract distribution and bioavailability of spiramycin in calves

Pharmacokinetic determinants of spiramycin and its distribution into the respiratory tract were studied in 2 groups of calves, 4 to 10 weeks old. Group-A calves (n = 4) were used to determine pharmacokinetic variables of spiramycin after IV (15 and 30 mg/kg of body weight) and oral administrations of the drug (30 mg/kg) and to measure distribution of spiramycin into nasal and bronchial secretions. Group-B calves (n = 4) were used to determine distribution of spiramycin into lung tissue and bronchial mucosa. Spiramycin disposition was best described by use of an open 3-compartment model. Mean (+/- SD) elimination half-life was 28.7 +/- 12.3 hours, and steady-state volume of distribution was 23.5 +/- 6.0 L/kg. Bio-availability after oral administration was 4 +/- 3%. High and persistent concentrations of spiramycin were achieved in the respiratory tract tissues and fluids. Tissue-to-plasma concentration ratio was 58 for lung tissue and 18 for bronchial mucosa at 3 hours after spiramycin administration and 137 and 49, respectively at 24 hours. Secretion-to-plasma concentration ratio was 4 for nasal secretions and 7 for bronchial secretions, and remained almost constant with time. Thus, spiramycin penetrates well into the respiratory tract, although the value in bronchial secretions is lower than that in lung tissues and bronchial mucosa. Calculations indicate that a loading dose of 45 mg/kg, administered IV, followed by a maintenance dose of 20 mg/kg, IV, once daily is required to maintain active concentrations of spiramycin against bovine pathogens in bronchial secretions.     

Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse

The pharmacokinetics and bioavailability of rifampin were determined after IV (10 mg/kg of body weight) and intragastric (20 mg/kg of body weight) administration to 6 healthy, adult horses. After IV administration, the disposition kinetics of rifampin were best described by a 2-compartment open model. A rapid distribution phase was followed by a slower elimination phase, with a half-life (t1/2[beta]) of 7.27 +/- 1.11 hours. The mean body clearance was 1.49 +/- 0.41 ml/min.kg, and the mean volume of distribution was 932 +/- 292 ml/kg, indicating that rifampin was widely distributed in the body. After intragastric administration of rifampin in aqueous suspension, a brief lag period (0.31 +/- 0.09 hour) was followed by rapid, but incomplete, absorption (t1/2[a] = 0.51 +/- 0.32 hour) and slow elimination (t1/2[d] = 11.50 +/- 1.55 hours). The mean bioavailability (fractional absorption) of the administered dose during the first 24 hours was 53.94 +/- 18.90%, and we estimated that 70.0 +/- 23.6% of the drug would eventually be absorbed. The mean peak plasma rifampin concentration was 13.25 +/- 2.70 micrograms/ml at 2.5 +/- 1.6 hours after dosing. All 6 horses had plasma rifampin concentrations greater than 2 micrograms/ml by 45 minutes after dosing; concentrations greater than 3 micrograms/ml persisted for at least 24 hours. Mean plasma rifampin concentrations at 12 and 24 hours after dosing were 6.86 +/- 1.69 micrograms/ml and 3.83 +/- 0.87 micrograms/ml, respectively. We tested 162 isolates of 16 bacterial species cultured from clinically ill horses for susceptibility to rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of norfloxacin in dogs after single intravenous and single and multiple oral administrations of the drug

Norfloxacin was given to 6 healthy dogs at a dosage of 5 mg/kg of body weight IV and orally in a complete crossover study, and orally at dosages of 5, 10, and 20 mg/kg to 6 healthy dogs in a 3-way crossover study. For 24 hours, serum concentration was monitored serially after each administration. Another 6 dogs were given 5 mg of norfloxacin/kg orally every 12 hours for 14 days, and serum concentration was determined serially for 12 hours after the first and last administration of the drug. Complete blood count and serum biochemical analysis were performed before and after 14 days of oral norfloxacin administration, and clinical signs of drug toxicosis were monitored twice daily during norfloxacin administration. Urine concentration of norfloxacin was determined periodically during serum acquisition periods. Norfloxacin concentration was determined, using high-performance liquid chromatography with a limit of detection of 25 ng of norfloxacin/ml of serum or urine. Serum norfloxacin pharmacokinetic values after single IV dosing in dogs were best modeled, using a 2-compartment open model, with distribution and elimination half-lives of 0.467 and 3.56 hours (harmonic means), respectively. Area-derived volume of distribution (Vd area) was 1.77 +/- 0.69 L/kg (arithmetic mean +/- SD), and serum clearance (Cls) was 0.332 +/- 0.115 L/h/kg. Mean residence time was 4.32 +/- 0.98 hour. Comparison of the area under the curve (AUC; derived, using model-independent calculations) after iv administration (5 mg/kg) with AUC after oral administration (5 mg/kg) in the same dogs indicated bioavailability of 35.0 +/- 46.1%, with a mean residence time after oral administration of 5.71 +/-2.24 hours. Urine concentration was 33.8 +/- 15.3 micrograms/ml at 4 hours after a single dose of 5 mg/kg given orally, whereas concentration after 20 mg/kg was given orally was 56.8 +/- 18.0 micrograms/ml at 6 hours after dosing. Twelve hours after drug administration, urine concentration was 47.4 +/- 20.6 micrograms/ml after the 5-mg/kg dose and 80.6 +/- 37.7 micrograms/ml after the 20/mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of phenobarbital in the horse

Pharmacokinetics of phenobarbital was examined in 6 mature horses after 12 mg of phenobarbital/kg of body weight was infused over 20 minutes. Biexponential decrease in serum phenobarbital concentrations was observed with a distribution-phase half-life of 0.101 +/- 0.086 hour (mean +/- SD) and a terminal-phase elimination half-life of 18.3 +/- 3.65 hours. The volume of distribution at steady state was 0.803 +/- 0.070 L/kg. Total body clearance of phenobarbital was 30.8 +/- 6.2 ml/h/kg. The high clearance in the horse seems to explain the markedly shorter half-life of phenobarbital in this species. Seemingly, 6.65 mg of phenobarbital/kg as a 20-minute infusion given every 12 hours would provide approximate peaks of 29 micrograms/ml and troughs of 15 micrograms/ml. A loading dose of 12 mg of phenobarbital/kg would be appropriate for this regimen.     

Pharmacokinetics of tylosin in broiler chickens

Biological availability and pharmacokinetic properties of tylosin were determined in broiler chickens after oral (p.o.) and intravenous (i.v.) administration at a dose of 10 mg/kg. The calculated bioavailability--F%, by comparing AUC values--p.o. and AUC--i.v., ranged from 30%-34%. After intravenous injection tylosin was rapidly distributed in the organism, showing elimination half-life (t1/2 beta) values of 0.52 h and distribution volume (Vd) of 0.69 L/kg, at a clearance rate (Cl) of 5.30 +/- 0.59 ml/min/kg. After oral administration, tylosin has a similar distribution volume (Vd = 0.85 L/kg), while the elimination half-life t1/2 beta of 2.07 h was four times bigger than after i.v. administration at Cl = 4.40 +/- 0.27 ml/min/kg. The obtained value tmax = 1.5 h for tylosin after oral administration indicates that using this antibiotic with drinking water in broiler chickens is the method of choice. However, a relatively low value Cmax = 1.2 micrograms/ml after oral administration of tylosin shows that dosing of this antibiotic in broiler chickens should be higher than in other food producing animals.     

Pharmacokinetics of phenobarbital in the cat following intravenous and oral administration.

Phenobarbital was administered to eight healthy cats as a single intravenous dose of 10 mg/kg. Serum phenobarbital concentrations were determined using an immunoassay technique. The intravenous data were fitted to one-, two- and three-compartment models. After statistical comparison of the three models, a two-compartment model was selected. Following intravenous administration, the drug was rapidly distributed (distribution half-life = 0.046 +/- 0.007 h) with a large apparent volume of distribution (931 +/- 44.8 mL/kg). Subsequent elimination of phenobarbital from the body was slow (elimination half-life = 58.8 +/- 4.21 h). Three weeks later, a single oral dose of phenobarbital (10 mg/kg) was administered to the same group of cats. A one-compartment model with an input component was used to describe the results. After oral administration, the initial rapid absorption phase (absorption half-life = 0.382 +/- 0.099 h) was followed by a plateau in the serum concentration (13.5 +/- 0.148 micrograms/mL) for approximately 10 h. The half-life of the terminal elimination phase (76.1 +/- 6.96 h) was not significantly different from the half-life determined for the intravenous route. Bioavailability of the oral drug was high (F = 1.20 +/- 0.120). Based on the pharmacokinetic parameters determined in this study, phenobarbital appears to be a suitable drug for use as an anticonvulsant in the cat.     

Body fluid and endometrial concentrations of ketoconazole in mares after intravenous injection or repeated gavage

After single oral administration of ketoconazole (30 mg/kg bodyweight [bwt]) in 50 ml of corn syrup to a healthy mare, the drug was not detected in serum. Ketoconazole in 0.2 N HC1 was administered intragastrically to six healthy adult horses in five consecutive doses of 30 mg/kg bwt at 12 h intervals. Ketoconazole concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid (CSF), urine and endometrium. Mean peak serum ketoconazole concentration was 3.76 micrograms/ml at 1.5 to 2 h after intragastric administration. Mean peak synovial concentration was 0.87 micrograms/ml 3 h after the fifth dose. Similarly, mean peritoneal concentration peaked 3 h after the fifth dose at 1.62 micrograms/ml. Mean endometrial concentrations peaked at 2.73 micrograms/ml 2 h after the fifth dose. Ketoconazole was detected in the CSF of only one of the six mares at a concentration of 0.28 micrograms/ml 3 h after the fifth dose. The highest measured concentration of ketoconazole in urine was 6.15 micrograms/ml 2 h after the fifth dose. A single intravenous injection of ketoconazole (10 mg/kg bwt) was given to one of the six mares; the overall elimination rate constant was estimated at 0.22/h and bioavailability after oral administration was 23 per cent.     

Pharmacokinetics and bioavailability of cephalothin in horse mares

The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/kg and accounted for elimination of about 10.1% of the administered dose. The volume of distribution at steady state averaged 151 mg/kg. Plasma protein binding of cephalothin at a concentration of 10 micrograms/ml averaged 17.9 +/- 2.5%. Cephalothin was rapidly metabolized to desacetylcephalothin. Maximum plasma desacetylcephalothin concentrations were observed in the blood samples collected 5 minutes after IV doses and averaged 22.9 micrograms/ml. The apparent half-life of desacetylcephalothin in plasma was 41.6 minutes and its renal clearance averaged 4.49 +/- 2.43 ml/min/kg. An average of 33.9% of the dose was recovered in the urine as desacetylcephalothin. The maximum plasma cephalothin concentration after IM administration was 11.3 +/- 3.71 micrograms/ml. The terminal half-life was 47.0 minutes and was longer than the half-life after IV administration. The bioavailability of cephalothin given IM ranged from 38.3% to 93.1% and averaged 65.0 +/- 20.5%.     

Pharmacokinetics and tissue residues of josamycin in fowls.

Josamycin is a macrolide antibiotic which is produced by fermentation of cultures of Streptomyces narbonensis. It was once administrated (18 mg/kg b. wt.) in fowls via intravenous, oral and intramuscular routes for determination of blood concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time-curve indicated a two compartments open model with an elimination half life value (t1/2 beta) of 1.83 +/- 0.06 hours. Both oral and intramuscular routes showed higher values, i.e. 2.33 +/- 0.13 and 2.85 +/- 0.17 hours. The lower apparent volume of distribution of Josamycin in fowls than one liter/kg elucidate higher distribution in blood than in tissues. Systemic bioavailability after both oral and intramuscular administration, i.e. 33.88 +/- 2.4 and 27.28 +/- 1.46% respectively, showed lower absorption from site of i.m. application. Josamycin was administered (18 mg/kg b. wt.) intramuscularly and orally once daily for 5 consecutive days. The drug peaked in serum 1 hour (intramuscular) and 2 hours (orally) after each dose. The recorded results revealed that serum level of Josamycin was higher after oral application (29.98 +/- 1.92 micrograms/ml) than after i.m. application. The drug persisted in the lung tissues and fat for 72 hours after administration and disappeared from all body tissues 96 hours after the last dose of repeated administration.     

Pharmacokinetics of norfloxacin and its N-desethyl- and oxo-metabolites in broiler chickens.

Norfloxacin was given to 2 groups of chickens (8 chickens/group) at a dosage of 8 mg/kg of body weight, IV and orally. For 24 hours, plasma concentration was monitored serially after each administration. Another group of chickens (n = 30) was given 8 mg of norfloxacin/kg orally every 24 hours for 4 days, and plasma and tissue concentrations of norfloxacin and its major metabolites desethylenenorfloxacin and oxonorfloxacin were determined serially after the last administration of the drug. Plasma and tissue concentrations of norfloxacin, desethylenenorfloxacin, and oxonorfloxacin were measured by use of high-performance liquid chromatography. Pharmacokinetic variables were calculated, using a 2-compartment open model. For norfloxacin, the elimination half-life (t1/2 beta) and the mean +/- SEM residence time for plasma were 12.8 +/- 0.59 and 15.05 +/- 0.81 hours, respectively, after oral administration and 8.0 +/- 0.3 and 8.71 +/- 0.23 hours, respectively, after IV administration. After single oral administration, norfloxacin was absorbed rapidly, with Tmax of 0.22 +/- 0.02 hour. Maximal plasma concentration was 2.89 +/- 0.20 microgram/ml. Oral bioavailability of norfloxacin was found to be 57.0 +/- 2.4%. In chickens, norfloxacin was mainly converted to desethylenenorfloxacin and oxonorfloxacin. Norfloxacin parent drug and its 2 major metabolites were widely distributed in tissues. Considerable tissue concentrations of norfloxacin, desethylenenorfloxacin, and oxonorfloxacin were found when norfloxacin was administered orally (8 mg/kg on 4 successive days). The concentration of the parent fluoroquinolone in fat, kidneys, and liver was 0.05 micrograms/g on day 12 after the end of dosing.     

Pharmacokinetics and bioavailability of doxycycline in fasted and nonfasted broiler chickens

The pharmacokinetics and the influence of food on the kinetic profile and bioavailability of doxycycline was studied after a single intravenous (i.v.) and oral dose of 10.0 mg/kg body weight in 7-week-old broiler chickens. Following i.v. administration the drug was rapidly distributed in the body with a distribution half-life of 0.21 +/- 0.01 h. The elimination half-life of 6.78 +/- 0.06 h was relatively long and resulted from both a low total body clearance of 0.139 +/- 0.007 L/h.kg and a large volume of distribution of 1.36 +/- 0.06 L/kg. After oral administration to fasted chickens, the absorption of doxycycline was quite fast and substantial as shown by the absorption half-life of 0.39 +/- 0.03 h, the maximal plasma concentration of 4.47 +/- 0.16 micrograms/mL and the time to reach the Cmax of 1.73 +/- 0.06 h. The distribution and the final elimination of the drug were slower than after i.v. administration. The absolute bioavailability was 73.4 +/- 2.5%. The presence of food in the intestinal tract reduced and extended the absorption (t1/2a = 1.23 +/- 0.21 h; Cmax = 3.07 +/- 0.23 micrograms/mL; tmax = 3.34 +/- 0.21 h). The absolute bioavailability was reduced to 61.1% +/- 4.4%.     

Bioavailability of spiramycin and lincomycin after oral administration to fed and fasted pigs

The disposition of spiramycin and lincomycin was measured after intravenous (i.v.) and oral (p.o.) administration to pigs. Twelve healthy pigs (six for each compound) weighing 16–43 kg received a dose of 10 mg/kg intravenously, and 55 mg/kg (spiramycin) or 33 mg/kg (lincomycin) orally in both a fasted and a fed condition in a three-way cross-over design. Spiramycin was detectable in plasma up to 30 h after intravenous and oral administration to both fasted and fed pigs, whereas lincomycin was detected for only 12 h after intravenous administration and up to 15 h after oral administration. The volume of distribution was 5.6 ± 1.5 and 1.1 ± 0.2 L/kg body weight for spiramycin and lincomycin, respectively. For both compounds the bioavailability was strongly dependent on the presence of food in the gastrointestinal tract. For spiramycin the bioavailability was determined to be 60% and 24% in fasted and fed pigs, respectively, whereas the corresponding figures for lincomycin were 73% and 41%. The maximum plasma concentration of spiramycin (C_max) was estimated to be 5 μg/mL in fasted pigs and 1 μg/mL only in fed pigs. It is concluded that an oral dose of 55 mg/kg body weight is not enough to give a therapeutically effective plasma concentration of spiramycin against species of Mycoplasma, Streptoccocus, Staphylococcus and Pasteurella multocida. The maximum plasma concentration of lincomycin was estimated to be 8 μg/mL in fasted pigs and 5 μg/mL in fed pigs, but as the minimum inhibitory concentration for lincomycin against Actinobacillus pleuropneumoniae and P. multocida is higher than 32 μg/mL a therapeutically effective plasma concentration could not be obtained following oral administration of the drug. For Mycoplasma the MIC₉₀ is below 1 μg/mL and a therapeutically effective plasma concentration of lincomycin was thus obtained after oral administration to both fed and fasted pigs.     

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.     

Pharmacokinetics and body fluid and endometrial concentrations of cefoxitin in mares

Four healthy adult mares were each given a single injection of sodium cefoxitin (20 mg/kg of body weight, IV), and serum cefoxitin concentrations were measured serially during a 6-hour period. The mean elimination rate constant was 1.08/hour and the elimination half-life was 0.82 hour. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.12 L/kg and 259 ml/hr/kg, respectively. Each mare and 2 additional mares were then given 4 consecutive IM injections of sodium cefoxitin (400 mg/ml) at a dosage of 20 mg/kg. Cefoxitin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 23.1 micrograms/ml 30 minutes after the 2nd injection. The highest mean synovial concentration was 11.4 micrograms/ml 1 hour after the 4th injection. The highest mean peritoneal concentration was 10.4 micrograms/ml 2 hours after the 4th injection. The highest mean endometrial concentration was 4.5 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 11,645 micrograms/ml. Cefoxitin did not readily penetrate the CSF. Bioavailability of cefoxitin given IM was 65% to 89% (mean +/- SEM = 77% +/- 5.9%). One of the 6 mares developed acute laminitis during the IM experiment.     

Pharmacokinetic interactions between flunixin and sulphadimidine in horses.

The pharmacokinetic aspects of sulphadimidine were studied in clinically healthy (control) and Flunixin-medicated horses after a single intravenous and oral administration of 100 mg/kg body weight. Plasma sulphadimidine concentration were determined by high-performance liquid chromatography (HPLC). Following the intravenous injection, all plasma sulphadimidine data were best approximated by a two-compartment open model using sequential, weight non-linear regression. Flunixin induced a 67% increase in the rate of sulphadimidine return to the central compartment from peripheral tissues (K21) and there were a trend to a 30% increase in K12. The sulphadimidine elimination half-life was decreased 21%, the Vdss was reduced by 18% and MRT was decreased by 20%. Following the oral administration, sulphadimidine was rapidly absorbed in control and Flunixin-medicated horses with absorption half-lives (t1/2 ab) of 0.5 and 0.43 hours respectively. The peak plasma concentration (Cmax) were 93.7 and 109 micrograms/ml attained at (tmax) 2.36 and 1.9 hours respectively. The elimination half-life after oral administration (t1/2 ab) was shorter in flunixin pre-medicated horses than in control ones. The systemic bioavalability percentages (F%) of sulphadimidine after oral administration of 100 mg/kg body weight was 79.3 and 71.2% in control and flunixin medicated horses, respectively. Therefore care should be exercised in the use of sulphadimidine in equine patients concurrently treated with flunixin.     

Serum and skin concentrations after multiple-dose oral administration of trimethoprim-sulfadiazine in dogs.

Six healthy adult mixed breed dogs were each given 5 oral doses of trimethoprim (TMP)/sulfadiazine (SDZ) at 2 dosage regimens: 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg every 24 hours (experiment 1) and every 12 hours (experiment 2). Serum and skin concentrations of each drug were measured serially throughout each experiment and mean serum concentrations of TMP and SDZ were determined for each drug for 24 hours (experiment 1) and 12 hours (experiment 2) after the last dose was given. In experiment 1, mean serum TMP concentration was 0.67 +/- 0.02 micrograms/ml, and mean skin TMP concentration was 1.54 +/- 0.40 micrograms/g. Mean serum SDZ concentration was 51.1 +/- 12.2 micrograms/ml and mean skin SDZ concentration was 59.3 +/- 9.8 micrograms/g. In experiment 2, mean serum TMP concentration was 1.24 +/- 0.35 micrograms/ml and mean skin TMP concentration was 3.03 +/- 0.54 micrograms/g. Mean serum SDZ concentration was 51.6 +/- 9.3 micrograms/ml and mean skin SDZ concentration was 71.1 +/- 8.2 micrograms/g. After the 5th oral dose in both experiments, mean concentration of TMP and SDZ in serum and skin exceeded reported minimal inhibitory concentrations of TMP/SDZ (less than or equal to 0.25/4.75 micrograms/ml) for coagulase-positive Staphylococcus sp. It was concluded that therapeutically effective concentrations in serum and skin were achieved and maintained when using the manufacturer's recommended dosage of 30 mg of TMP/SDZ/kg (5 mg of TMP/kg and 25 mg of SDZ/kg) every 24 hours.     

Pharmacokinetics of metronidazole and its concentration in body fluids and endometrial tissues of mares.

Serum concentrations of metronidazole were determined in 6 healthy adult mares after a single IV injection of metronidazole (15 mg/kg of body weight). The mean elimination rate (K) was 0.23 h-1, and the mean elimination half-life (t1/2) was 3.1 hours. The apparent volume of distribution at steady state was 0.69 L/kg, and the clearance was 168 ml/h/kg. Each mare was then given a loading dose (15 mg/kg) of metronidazole at time 0, followed by 4 maintenance doses (7.5 mg/kg, q 6 h) by nasogastric tube. Metronidazole concentrations were measured in serial samples of serum, synovia, peritoneal fluid, and urine. Metronidazole concentrations in CSF and endometrial tissues were measured after the fourth maintenance dose. The highest mean concentration in serum was 13.9 +/- 2.18 micrograms/ml at 40 minutes after the loading dose (time 0). The highest mean synovial and peritoneal fluid concentrations were 8.9 +/- 1.31 micrograms/ml and 12.8 +/- 3.21 micrograms/ml, respectively, 2 hours after the loading dose. The lowest mean trough concentration in urine was 32 micrograms/ml. Mean concentration of metronidazole in CSF was 4.3 +/- 2.51 micrograms/ml and the mean concentration in endometrial tissues was 0.9 +/- 0.48 micrograms/g at 3 hours after the fourth maintenance dose. Two mares hospitalized for treatment of bacterial pleuropneumonia were given metronidazole (15.0 mg/kg, PO, initially then 7.5 mg/kg, PO, q 6 h), while concurrently receiving gentamicin, potassium penicillin, and flunixin meglumine IV. Metronidazole pharmacokinetics and serum concentrations in the sick mares were similar to those obtained in the healthy mares.