Comparative pharmacokinetics,bioavailability and renal clearance of five parenteral oxytetracycline‐20% formulations in dairy cows

Summary

Oxytetracycline (OTC) concentrations in plasma and milk of dairy cows were determined following a single intramuscular injection of five oxytetracycline‐20% formulations at a dosage of approximately 10 mg/kg. For obtaining pharmacokinetic reference parameters, one 10% OTC formulation was administered intravenously. The five 20% formulations were compared and evaluated pharmacokinetically with respect to absorption rate, peak plasma and milk OTC concentrations, biological half‐life, and relative bioavailability. The mean maximum plasma OTC concentrations varied between 4.5 and 6.8 μg/ml and were achieved between 5 and 10 h p.i., depending on the formulation involved. The mean maximum milk concentrations, ranging from 1.12 to 1.92 μg/ml, were achieved 12 to 24 h p.i. A plasma OTC concentration exceeding 0.5 μg/ml was maintained for 48 h to 70 h, and in milk for 33 to 49 h, depending on the formulation involved.

Formulations exhibiting the lowest clinically noticeable irritation showed the highest peak plasma OTC concentrations and the best bioavailability. Among the formulations the calculated withholding periods for milk were in the range of 3 to 4 days and for edible tissues of 9 to 14 days. The OTC and creatinine clearances were significantly correlated to each other and to the urinary flow. OTC was excreted predominantly by glomerular filtration, partly by tubular secretion minus urogenital (distal renal tubuli and bladder) reabsorption.     

Comparative pharmacokinetics and bioavailability of eight parenteral oxytetracycline‐10% formulations in dairy cows

Summary

In plasma and milk the oxytetracycline (OTC) concentrations were determined following a single intramuscular administration of eight 10%‐formulations to dairy cows at a dose of approximately 5 mg/kg. Two of these formulations were injected intravenously to obtain reference values of the drug's pharmacokinetic parameters. The eight formulations were compared and evaluated pharmacokinetically with respect to absorption rate, peak plasma and milk OTC concentrations, biological half‐life, and relative bioavailability. The mean maximum plasma OTC concentrations, ranging from 2.0 to 4. 1 μg/ml, were achieved between 4 and 12 hours post injection, depending on the formulation involved. The mean maximum milk OTC concentrations, in the range between 0.92 and 1.43 μg/ml, were achieved 12 to 24 h p. i. The OTC milk concentration‐time profile ran parallel to the OTC plasma concentration‐time profile.

After intravenous administration the time for the appearance of OTC in milk was shorter (1–2 hours p.i.), the peak milk OTC concentration was higher (1.7–1.9 μg/ml) and achieved earlier (6–8 h p.i.). and the OTC persistence in milk shorter than after i.m. administration. Formulations exhibiting the lowest clinically noticeable irritation showed the most favourable pharmacokinetic characteristics: rapid absorption with the highest peak plasma OTC concentrations and good bioavailability.

The plasma and milk protein binding for OTC was respectively 71.7± 7.4% and 84.8 ± 5.45%. Withdrawal times for milk and edible tissues are presented on the basis of preset tolerance or detection limits.     

Plasma concentrations of oxytetracycline in swine after administration of the drug intramuscularly and orally in feed

Four pigs were used in a 2 X 2 crossover study to determine plasma oxytetracycline (OTC) concentration and OTC pharmacokinetic variables after IM administration of 2 OTC preparations--long acting OTC and a 100-mg of OTC/ml solution (OTC-LA and OTC-100, respectively)--at a dosage of 20 mg/kg of body weight. In a second study, 3 additional pigs were given ad libitum access to feed containing pure OTC (0.55 g/kg of feed). The mean (+/- SD) peak plasma OTC concentration after OTC-LA administration was 6.0 +/- 2.2 micrograms/ml at 30 minutes; the mean peak plasma OTC concentration after OTC-100 administration was 6.7 +/- 3.4 micrograms/ml at 90 minutes. Mean plasma OTC concentration after oral OTC administration in feed peaked at 0.4 micrograms/ml 48 hours after access to OTC-medicated feed and decreased to 0.25 micrograms/ml by the end of that study. Mean plasma OTC concentration was maintained at greater than 0.5 micrograms/ml for less than 48 hours after OTC-LA administration and for less than 36 hours after OTC-100 administration. Mean plasma OTC concentration decreased to less than 0.2 micrograms/ml by 72 hours after IM administration of either product. Calculation of area under the plasma OTC concentration-time curve (AUC) did not reveal significant difference between the 2 OTC formulations. There also was not significant difference (between OTC-LA and OTC-100) in the value of the disappearance rate constant after administration of either OTC formulation. The data did not indicate significant pharmacologic advantage of OTC-LA, compared with OTC-100, when either formulation was administered IM at a dosage of 20 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of four slow-release theophylline formulations in the Beagle dog

Theophylline was administered to six Beagles intravenously (Aminophyllin Injectable, Searle Laboratories) and orally as four sustained-release formulations (Choledyl -SA Tablets, Parke-Davis; Theo-Dur Tablets, Key Pharmaceuticals; Theo-24 Capsules, Searle Laboratories, and Slo-bid Gyrocaps, William H. Rorer, Inc.). Values were determined for mean residence time, mean absorption time, absolute bioavailability, time to peak plasma concentration, and peak plasma concentration normalized to a theophylline dose of 20 mg/kg. In this order the values found for each formulation were: Choledyl (10.2 +/- 1.8 h, 2.8 +/- 2.2 h, 63 +/- 10%, 3.9 +/- 1.0 h, 10 +/- 1.1 micrograms/ml), Theo-Dur (12.1 +/- 5.2 h, 4.9 +/- 5.3 h, 76 +/- 18% 4.7 +/- 3.1 h, 12 +/- 3.7 micrograms/ml), Theo-24 (15.6 +/- 8.9 h, 8.1 +/- 8.4 h, 30 +/- 16%, 3.6 +/- 1.7 h, 3.5 +/- 1.3 micrograms/ml), and Slo-bid (11.9 +/- 1.9 h, 4.4 +/- 1.3 h, 60 +/- 9%, 4 +/- 1.1 h, 8.6 +/- 0.8 micrograms/ml). Choledyl, Theo-Dur and Slo-bid appear to have absorption characteristics which, if given twice daily, would maintain therapeutic plasma concentrations of theophylline between 10 and 20 micrograms/ml in the dog. Of these, Theo-Dur was predicted to provide the least peak:trough fluctuation in theophylline plasma concentrations.     

Pharmacokinetics and renal clearance of oxytetracycline in piglets following intravenous and oral administration

The pharmacokinetics of oxytetracycline (OTC) in three weaned piglets was studied following three routes of administration: intravenously, orally as drench, both at a dose of 20 mg/kg, and orally as medicated (400 ppm OTC) pelleted feed administered during 3 consecutive days. Analysis of the intravenous data according to the three compartment pharmacokinetic model revealed that OTC was well distributed in the body (Vf: 1.62 l/kg), had an overall body clearance of 0.25 litre/kg/h, and the elimination half-lives were in the range between 11.6 and 17.2 hrs. The mean OTC binding to plasma proteins was 75.5 +/- 4%. Following the drench route of administration the maximum plasma OTC concentration was achieved between 1 and 5 h post application and ranged between 1.18 and 1.41 micrograms/ml. The mean maximum plasma OTC concentration during medicated feed administration was 0.20 +/- 0.06 microgram/ml, which was achieved approximately 30 hours after the onset of the administration. A steady state OTC plasma level (approximately 0.2 microgram/ml) was maintained till the end of the trial. Within 48 hours after cessation of medicated feed administration the plasma OTC levels were beneath 0.06 microgram/ml. The mean OTC bioavailabilities of the oral routes were low: after the drench route of administration 9.0 +/- 0.67%, and after medicated pelleted feed administration 3.69 +/- 0.8%. The mean OTC renal clearances of each piglet ranged between 10.1 and 13.9 ml/min/kg (based on free OTC plasma fractions). The renal OTC clearance values were urine flow dependent in all piglets and significantly correlated with the renal creatinine clearance (P less than 0.005), being 3-5 times higher than the latter. It is concluded that in piglets OTC is excreted mainly by glomerular filtration and partly by tubular secretion. The potential clinical efficacy of 400 ppm OTC as medicated feed with respect to treatment, e.g. atrophic rhinitis, is discussed.     

Pharmacokinetic, residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants

The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicol Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 micrograms/ml) and 36% larger areas under the plasma concentration-time curves than product B, whereas their absorption and elimination half-lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug. The maximum CAP concentration in milk was for product B equal to, and for product A 80% of, the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra-trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean-up procedure. Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine. Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited.(ABSTRACT TRUNCATED AT 250 WORDS)     

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).     

Pharmacokinetics of sulphanilamide and its three acetyl metabolites in dairy cows and calves

An intravenous low dosage of sulphanilamide (SAA) (14.0 mg/kg) to 6 pre-ruminant calves revealed a biphasic SAA plasma disposition with a mean elimination half-life of 4.1 h. The main metabolite in plasma was N4-acetylsulphanilamide (N4), which 4 hours after injection exceeded the parent SAA plasma concentration. Urinary recovery of SAA was 10 to 16% of the dose; of N4, it was at least 69%. Traces of the N1-acetyl (N1) metabolite and the doubly acetylated derivative (N1N4) were present in urine. The renal clearances of the N1 and N4 metabolites showed a tubular secretion pattern, which was at least 2 to 6 times higher than that of SAA. A single high oral SAA dose of 200 mg/kg to 3 dairy cows resulted in extensive metabolism of SAA into N4, N1, and N1N4 metabolites; their mean maximum plasma concentrations were 64, 48, 0.72 and 24 micrograms/ml, respectively. The mean disposition half-life of SAA in plasma and milk was 10 h. In milk the metabolite concentrations exceeded those in plasma; the N4 and N1N4 metabolite concentrations in milk exceeded that of SAA. The mean maximum concentrations of SAA, N4, N1, and N1N4 in milk were 52, 89, 2.3, and 98 micrograms/ml, respectively. For SAA and its metabolites, the binding to plasma and milk proteins was determined. No glucuronide or sulphate conjugates of SAA and its acetyl metabolites could be found in plasma, milk, or urine. Based on the sensitivity of the bioassay (0.2 micrograms SAA/ml), a withholding time of 5 days was suggested for milk following single oral SAA dosage of 200 mg/kg.     

Pharmacokinetics of oxytetracycline hydrochloride in rabbits

Pharmacokinetics of oxytetracycline HCl (OTC) was studied in rabbits. After 10 mg of OTC/kg of body weight was administered IV, the distribution half-life was 0.06 hour, terminal half-life was 1.32 hours, volume of distribution area was 0.861 L/kg, and total body clearance was 0.434 L/kg/h. After 10 mg of OTC/kg was given IM, the absorption half-life was 2.09 hours, extent of absorption was 71.4%, and total body clearance of the absorbed fraction was 0.576 L/kg/h. Based on these kinetic data, a dosage of 15 mg of OTC/kg, every 8 hours was developed. This dose given IM for 7 consecutive days resulted in observed steady-state maximum and minimum concentrations (mean +/- SD) of 4.7 +/- 0.3 micrograms/ml and 3.2 +/- 0.6 micrograms/ml, respectively. Twice this dose (30 mg of OTC/kg, every 8 hours) given IM caused anorexia and diarrhea.     

Pharmacokinetics and residues in milk of oxytetracyclines administered parenterally to dairy goats

OBJECTIVE: To determine for two commercial preparations of oxytetracycline (OTC) the pharmacokinetic behaviour, the presence of detectable milk residues and the penetration in milk of OTC administered by intravenous (IV) (conventional formulation [CF]) and intramuscular (IM) routes (CF and long-acting [LA] formulations) in goats producing milk. The effects of these formulations on plasma activity values of creatine kinase (CK) and lactate dehydrogenase (LDH) were also determined as indicators of tissue damage. PROCEDURE: Five healthy lactating goats producing 1.5+/-0.5 L/d milk and weighing 56.0+/-4.8 kg were used. Single doses of OTC chlorhydrate (CF) were administered (20 mg OTC/kg) by IV (Trial 1 IV) and IM (Trial 1 IM) routes and OTC dehydrate (LA) by the IM route. The same goats were first given IV CF, then IM CF followed by IM LA with 3 weeks between each treatment. Blood and milk samples were taken. The quantification of OTC was performed by HPLC and the plasma activities of CK and LDH enzymes were determined by spectrophotometry. The presence of OTC residues in milk was determined by a commercial reagent. The plasma pharmacokinetic parameters were calculated using a two-compartment model. RESULTS: Estimates of kinetic variables following IV administration were: Vss= 400.0+/-120.0 mL/kg and CL= 110.0+/-14.0 (mL/h)/kg. The t(fi) for IV= 3.0+/-0.3 h; IM, CF = 10.5+/-2.1 h and IM, LA = 15.1+/-3.1 h. The concentration of OTC in milk at 48 h was: IV= 0.6+/-0.4; IM CF= 1.1+/-0.2 and at 72 h (IM LA)= 0.6+/-0.1 microg/mL and the penetration in milk of OTC was: IV= 70.0+/-18.0; IM CF= 79.0+/-14.0 and IM LA= 66.0+/-6.0%. The areas under the curve of CK and LDH activities in plasma were calculated by the trapezoidal method. Values of CK and LDH IM, LA were greater (P < 0.05) than those observed for IM, CF at 2 and 3 days after administration of the antibiotic. Finally, the bioavailability of OTC CF = 92.0+/-22.0 and LA= 78.0+/-23.0% was suitable for its usage by the IM route in lactating goats. CONCLUSION: Plasma concentration-time values of OTC administered parenterally in production dairy goats showed similar bioavailability for the two pharmaceutical preaprations. The presence of detectable residues in milk indicates that milk should not be used for human consumption for 2 and 3 days after administration of conventional and long-acting formulations, respectively. The increments in CK and LDH activities after the IM administration of LA are consistent with the presence of tissue damage provoked by the pharmaceutical preparations at the injection site.     

Intra-abdominal versus intramuscular application of two ampicillin preparations in cows

Plasma ampicillin concentrations were determined in a cross-over trial involving five cows after single intramuscular or intra-abdominal administration of sodium ampicillin (10 mg/kg) and ampicillin anhydrate (40 mg/kg). After injection of sodium-ampicillin, high plasma concentrations were reached within 10 min; Cmax following intramuscular injection was 9.1 micrograms/ml and after intra-abdominal injection 7.5 micrograms/ml. Urine concentrations of ampicillin were low after 24 h (1-1.5 micrograms/ml). No significant changes in blood leucocyte numbers, plasma zinc, iron or fibrinogen levels occurred. After injection of ampicillin anhydrate 1 h elapsed before maximum plasma levels were obtained; Cmax was 5.4 micrograms/ml after intramuscular and 6.7 micrograms/ml after intra-abdominal administration. Urine concentrations were very high (238-303 micrograms/ml) after 24 h and stayed above 1 microgram/ml for 6 days. After administration of ampicillin anhydrate a significant increase in blood neutrophils (P less than 0.01) and a significant increase in plasma fibrinogen was measured after intramuscular and intra-abdominal injection (P less than 0.05). A significant decrease in plasma zinc concentration after intra-abdominal injection occurred (P less than 0.05). In abdominal surgery in cows in which contamination cannot be prevented, and practical objections inhibit preoperative administration, intramuscular or intra-abdominal administration during surgery of sodium ampicillin seems justified. Ampicillin anhydrate should not be used intra-abdominally.     

Pharmacokinetic disposition of an immediate-release aminophylline and a sustained-release theophylline formulation in the horse

The pharmacokinetic disposition of theophylline was determined by high-performance liquid chromatographic analysis of plasma samples from six healthy, adult horses following the administration of intravenous aminophylline (dosed at 9.94 mg/kg as theophylline), immediate-release aminophylline tablets (dosed at 9.94 mg/kg as theophylline), and sustained-release theophylline tablets (dosed at 20 mg/kg). The elimination rate constant (lambda z), apparent volume of distribution (Vz), and clearance (Cl) determined by compartmental analysis of the intravenous data were 0.07 +/- 0.01 h-1, 0.80 +/- 0.06 l/kg, and 0.06 +/- 0.01 l/kg/h (mean +/- SD), respectively. Mean residence time determined by statistical moment theory of the oral data was different (P less than 0.05) for the immediate-release aminophylline (13.8 +/- 2.8 h) and sustained-release theophylline (18.2 +/- 2.3 h) formulation. Immediate-release aminophylline tablets quickly achieved peak theophylline plasma concentration of 11.51 +/- 1.4 micrograms/ml at 1.6 +/- 0.6 h while the sustained-release theophylline tablets were more slowly absorbed and achieved peak theophylline concentrations of 17.20 +/- 1.3 micrograms/ml at 7.3 +/- 1.0 h. Absolute bioavailability was 87% for the immediate-release and 97% for the sustained-release formulation. Using the principle of superposition, a loading dose of 20 mg/kg of the sustained-release formulation followed by maintenance doses of 15 mg/kg every 24 h was predicted to achieve trough-peak theophylline plasma concentrations between 6 and 17 micrograms/ml.     

Comparative pharmacokinetics of oxytetracycline in rainbow trout (Salmo gairdneri) and African catfish (Clarias gariepinus)

A comparative pharmacokinetic study was conducted in rainbow trout (Salmo gairdneri) and African catfish (Clarias gariepinus) following intravenous (i.v.) and intramuscular (i.m.) administration of oxytetracycline (OTC) at a dose rate of 60 mg/kg body weight. Trout and catfish were kept in aerated tap water in tanks at constant temperatures of 12 degrees C and 25 degrees C, respectively. The two- and three-compartment open models adequately described plasma drug disposition in African catfish and rainbow trout respectively, following i.v. OTC administration. Compared to catfish (COP = 86 +/- 10 micrograms/ml) an eightfold higher extrapolated zero time concentration was obtained in trout (COP = 753 +/- 290 micrograms/ml). A significant difference was observed with respect to the relatively large apparent distribution volumes (Vd(area] after i.v. OTC administration (trout, mean value: 2.1 l/kg; catfish, mean value: 1.3 l/kg). The mean final elimination half-lives of both fish species were greater than previously reported in mammals (trout, 89.5 h; catfish, 80.3 h). A mean maximum plasma concentration (Cmax = 56.9 micrograms/ml) was obtained in trout at 4 h after i.m. administration of OTC. In catfish a lower Cmax of 43.4 micrograms/ml was determined at about 7 h. No significant difference was observed with respect to bioavailability following i.m. administration of OTC (trout, 85%; catfish, 86%).     

Sustained-release theophylline pharmacokinetics in the cat

Theophylline was administered in a three-way crossover design study to six cats intravenously (Aminophylline USP, Invenex Laboratories, Chagrin Falls, OH) and orally as two sustained-release formulations (Slo-bid Gyrocaps (SB), William H. Rorer, Inc., Fort Washington, PA; Theo-Dur Tablets (TD), Key Pharmaceuticals, Miami, FL). Values were determined for mean residence time (SB = 19.4 +/- 3.2 h; TD = 15.8 +/- 4.8 h), mean absorption time (SB = 8.0 +/- 2.3 h; TD = 4.8 +/- 2.3 h), absolute bioavailability (SB = 82 +/- 27%; TD = 76 +/- 38%), and time to peak plasma concentrations (SB = 8 h; TD = 8 h). After normalization to a dose of 25 mg/kg, the average peak plasma concentrations were also predicted (SB = 10.5 +/- 3.4 micrograms/ml; TD = 14.3 +/- 6.7 micrograms/ml). Slo-bid was predicted to provide the least peak:trough fluctuation in theophylline concentrations. Slo-bid and Theo-Dur appear to have pharmacokinetic characteristics which, if given once-daily, would maintain plasma theophylline concentrations of 5-20 micrograms/ml in the cat.     

Acyclovir (Zovirax®) pharmacokinetics in Quaker parakeets, Myiopsitta monachus

The pharmacokinetics of intravenous (i.v.) and intramuscular (i.m.) single-dose administration of acyclovir were determined in Quaker parakeets. After i.v. injection at a dose of 20 mg/kg of acyclovir, elimination half-life was estimated at 0.65 h, volume of distribution at steady state was 627.65 ml/kg, and clearance was 11.22 ml/kg/min. The estimated pharmacokinetic values after i.m. injection at a dose of 40 mg/kg of acyclovir were an elimination half-life of 0.71 h and a bioavailability of 90.1%. The peak plasma acyclovir concentration occurred at 15 min when the drug was administered i.m. Plasma concentrations of acyclovir were undetectable 4-6 h after i.v. administration and 6-8 h after i.m. administration. Oral (capsules) and intravenous (sodium salt) formulations of acyclovir were given by gavage at 80 mg/kg. Peak concentrations with the sodium salt formulation were lower and developed more slowly than with the capsules. In studies designed to detect excessive drug accumulation or adverse side effects, acyclovir was administered i.m. at 40 mg/kg every 8 h for 7 days. Plasma concentrations were determined 15 min after (peak) and just prior to drug administration (trough). In another study acyclovir was gavaged at a dose of 80 mg/kg every 8 h for 4 days. Acyclovir plasma concentrations were determined just prior to and 2 h after drug administration. In both experiments, the birds maintained normal appetite and weight and did not exhibit excessive drug accumulation. Acyclovir plasma concentrations ranging from 2.07 +/- 1.09 micrograms/ml to 3.93 +/- 1.13 micrograms/ml were maintained for 4 days when acyclovir was administered in the feed and water (sole source of food and water).(ABSTRACT TRUNCATED AT 250 WORDS)     

Penetration of some antibiotics into the lacrimal fluid of sheep

Antibiotic concentrations were determined in the lacrimal fluid of sheep following subcutaneous application of penicillin/ dihydrostreptomycin into the lower eyelid, and intramuscular administration of spiramycin base, tiamulin, and oxytetracycline formulations. The penetration of penicillin and dihydrostreptomycin into the lacrimal fluid was poor. The spiramycin and tiamulin concentrations in the lacrimal fluid were 10‐ and 4‐fold higher than in the serum. The peak spiramycin concentration in the lacrimal fluid was 3.4 ±0.8 μg/ml at 8 h post injection (p.i.) and the drug could be detected at least 72 h p. i. For tiamulin and oxytetracycline (OTC) peak concentrations of 1.53 ±0.70 and 1.88 ±1.9 μg/ml, respectively, were achieved in the lacrimal fluid and these drugs could be detected 25 to 30 h p.i. The OTC and tiamulin concentration‐time curves for lacrimal fluid and serum were parallel, whereas for the spiramycin appearance in the lacrimal fluid was delayed.     

Antibiotic aerosolization: tissue and plasma oxytetracycline concentrations in parakeets

Oxytetracycline hydrochloride (OTC) was delivered to adult parakeets by aerosolization using a DeVilbiss model 65 ultrasonic nebulizer. Trachea, lung, and plasma concentrations were ascertained at 1, 2, 4, 6, and 8 hours postaerosolization (PA). An average of 284 ml of a solution containing 2 mg OTC/ml was aerosolized over a 1-hour period into a 0.0596 M3 chamber containing 10 parakeets. The trachea and lung concentrations were more than 10 micrograms/g at 1 and 2 hours PA, had decreased to approximately 3 micrograms/g by 4 hours PA, and were below 2 micrograms/g by 8 hours. The plasma concentration never exceeded 2.6 micrograms/ml and was at 1.6 micrograms/ml by 8 hours. This study demonstrates that it is possible to achieve therapeutic concentrations of OTC by aerosolization in lung and trachea, but treatment may need to be repeated every 4-6 hours. Since the plasma concentration never reached high levels, aerosolization under the conditions of this study is not an effective way to treat systemic infections outside the respiratory tract.     

A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse

The biopharmaceutical properties of four fuced trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 ± 0.48 h for a commercial paste (l), and at 1.84 ± 0.66 h and 1.95 ± 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (± SD) were 1.72 ± 0.36 μg/ml, 1.42 ± 0.37 μg/ml and 1.31 ± 0.36 μ g/d, and mean peak plasma SDZ concentrations 12.11 ± 4.5 5 μg/ml, 12.72 ± 3.47 μg/ml and 15.45 ± 4.74 μg/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 ± 20.3%, 57.7 ±21.6% and 60.9 f 18.9% and of SDZ 57.6 ± 14.8%, 59.3 ± 19.5% and 65.9 ± 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (It 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span. No adverse effects were seen following i.v. and oral administration. In considering the pharmacokinetic data in combination with in vitro antibacterial sensitivity data, it is concluded that treatment at a dose of 5 mg/kg TMP and 25 mg/kg SDZ with a dosing interval of 12 h can be regarded as therapeutically effective for susceptible bacteria (MIC₉₀ 0.25/4.75) for all three oral formulations. It is concluded that neither the formulation nor the addition of different excipients result in significantly different bioavailabilities.     

Pharmacokinetics of sodium cephapirin in lactating dairy cows

Sodium cephapirin was administered (10 mg/kg of body weight, IM) at 8-hour intervals in 4 consecutive doses to each of 6 lactating dairy cows. Blood, normal milk, mastitic milk, urine, and endometrial tissue samples were collected serially. Mean peak cephapirin concentrations in serum were 13.3 micrograms/ml 10 minutes after the 1st injection and were 15.8 micrograms/ml 20 minutes after the 4th injection (post[initial]injection hour [PIH] 24.33). The overall elimination rate constant value was 0.66/h and plasma clearance was 760 ml/h/kg. Mean peak cephapirin concentration in normal milk was 0.11 microgram/ml at PIH 2 and mean peak cephapirin concentration in mastitic milk was 0.18 microgram/ml at PIH 4. Cephapirin was not detected in the endometrium. The highest concentration of cephapirin in urine was 452 micrograms/ml, 2 hours after the 4th dose (PIH 26).     

Pharmacokinetics and renal clearance of oxytetracycline in piglets following intravenous and oral administration

Summary

The pharmacokinetics of oxytetracycline (OTC) in three weaned piglets was studied following three routes of administration: intravenously, orally as drench, both at a dose of 20 mg/kg, and orally as medicated (400 ppm OTC) pelleted feed administered during 3 consecutive days. Analysis of the intravenous data according to the three compartment pharmacokinetic model revealed that OTC was well distributed in the body (Vie 1.621/kg), had an overall body clearance of 0.25 litre/kg/h, and the elimination half‐lives were in the range between 11.6 and 17.2 hrs.

The mean OTC binding to plasma proteins was 75.5 ± 4%. Following the drench route of administration the maximum plasma OTC concentration was achieved between 1 and 5 h post application and ranged between 1.18 and 1.41 μg/ml. The mean maximum plasma OTC concentration during medicated feed administration was 0.20 ± 0.06 μg/ml, which was achieved approximately 30 hours after the onset of the administration. A steady state OTC plasma level (approximately 0.2 μg/ml) was maintained till the end of the trial. Within 48 hours after cessation of medicated feed administration the plasma OTC levels were beneath 0.06 μg/ml. The mean OTC bioavailabilities of the oral routes were low: after the drench route of administration 9.0 ± 0.67%, and after medicated pelleted feed administration 3.69 ± 0.8%.

The mean OTC renal clearances of each piglet ranged between 10.1 and 13.9 ml/min/kg (based on free OTC plasma fractions). The renal OTC clearance values were urine flow dependent in all piglets and significantly correlated with the renal creatinine clearance (P< 0.005), being 3–5 times higher than the latter. It is concluded that in piglets OTC is excreted mainly by glomerular filtration and partly by tubular secretion. The potential clinical efficacy of 400 ppm OTC as medicated feed with respect to treatment, e.g. atrophic rhinitis, is discussed.