Pharmacokinetics of flunixin meglumine in lactating cattle after single and multiple intramuscular and intravenous administrations.

The pharmacokinetics of flunixin were studied in 6 adult lactating cattle after administration of single IV and IM doses at 1.1 mg/kg of body weight. A crossover design was used, with route of first administration in each cow determined randomly. Plasma and milk concentrations of total flunixin were determined by use of high-pressure liquid chromatography, using an assay with a lower limit of detection of 50 ng of flunixin/ml. The pharmacokinetics of flunixin were best described by a 2-compartment, open model. After IV administration, mean plasma flunixin concentrations rapidly decreased from initial concentrations of greater than 10 micrograms/ml to nondetectable concentrations at 12 hours after administration. The distribution phase was short (t1/2 alpha, harmonic mean = 0.16 hours) and the elimination phase was more prolonged (t1/2 beta, harmonic mean = 3.14 hours). Mean +/- SD clearance after IV administration was 2.51 +/- 0.96 ml/kg/min. After IM administration, the harmonic mean for the elimination phase (t1/2 beta) was prolonged at 5.20 hours. Bioavailability after IM dosing gave a mean +/- SD (n = 5) of 76.0 +/- 28.0%. Adult, lactating cows (n = 6) were challenge inoculated with endotoxin as a model of acute coliform mastitis. After multiple administration (total of 7 doses; first IV, remainder IM) of 1.1 mg/kg doses of flunixin at 8-hour intervals, plasma flunixin concentrations were approximately 1 microgram/ml at 2 hours after each dosing and 0.5 micrograms/ml just prior to each dosing. Flunixin was not detected in milk at any sampling during the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Elimination of salicylic acid in goats and cattle.

Sodium salicylate was administered to cattle and goats IV and PO according to a crossover design. Total urinary excretion of SA and its metabolites was measured for 3 days after dosing. Salicyluric acid (SUA) was the only metabolite detected in urine of either species. Recovery of sodium salicylate and SUA in goats amounted to 67.9 and 34.6% of the dose, respectively, after IV administration. After oral dosing, total recoveries were 30.2% (sodium salicylate) and 71.7% (SUA) of dose. By comparison, cattle excreted significantly (P less than 0.05) less sodium salicylate (54.0%) and more SUA (49.9%) after IV dosing. The same pattern was observed after oral administration, wherein cattle excreted less than 12% as sodium salicylate and more than 99% as SUA. In both species, almost 90% of the drug excreted as sodium salicylate was found in urine within the first 12 hours after an IV dose and within 24 hours after oral dosing. The excretion of SUA was somewhat slower in both species, especially after oral administration. The data suggested that there were only quantitative differences in the metabolism and elimination of sodium salicylate between the 2 species, with cattle excreting a higher proportion of the drug as the glycine conjugate SUA.

Distribution of chloramphenicol in the genital tract of postpartum cows.

Chloramphenicol was administered by constant IV infusion to 7 healthy postpartum cows at rates predicted to approach a steady-state plasma concentration of 5 micrograms/ml. After 8 hours of constant IV infusion, uterine tissues were removed surgically and were assayed for chloramphenicol concentrations. Mean plasma-to-tissue ratios of chloramphenicol concentrations were 3.05, 3.63 (6 cows only), and 3.22 for caruncles, endometrium, and uterine wall, respectively. Plasma-to-tissue ratios of the 3 tissues were not significantly different (P greater than 0.10). Intrauterine (IU) injections of chloramphenicol (20 mg/kg of body weight) were administered to 3 healthy post-partum cows. The mean value of the fraction of the drug absorbed from the uteri of these cows was 0.40. Mean concentrations of chloramphenicol were 43.8 micrograms/g in caruncles, 34.6 micrograms/g in endometrium, 2.8 micrograms/g in uterine wall, and 2.9 micrograms/ml in plasma 8 hours after IU injections. Chloramphenicol has now been banned for use in food-producing animals in the United States because of its potential for causing toxicosis in human beings. It is illegal to use chloramphenicol in food-producing animals in the United States and in some other countries as well. This includes use by the IU route of administration because chloramphenicol and most drugs are absorbed from the uterus into the bloodstream and are distributed to milk and tissues.

Hyperglycemia and hypoinsulinemia during xylazine-ketamine anesthesia in Thoroughbred horses.

Plasma glucose and serum insulin concentrations in Thoroughbreds administered xylazine hydrochloride (1.1 mg/kg; IV) and ketamine hydrochloride (2.2 mg/kg; IV) at dosages sufficient to induce short periods of recumbency and anesthesia were measured. Samples of blood were collected from 6 adult horses before, during, and after the anesthetic period. Plasma glucose (mg/dl) was significantly increased above control (-30 minute concentration) from 15 to 150 minutes after xylazine administration with the peak value occurring at 30 minutes. Serum insulin (microU/ml) was significantly decreased from control from 5 to 90 minutes after xylazine administration, with the nadir occurring at 15 minutes. The alterations in plasma glucose and serum insulin concentrations in xylazine-ketamine-anesthetized horses were similar to the changes in xylazine-sedated horses.

Disposition of fenbendazole in the goat.

The disposition of fenbendazole was studied in goats after oral or IV administration. Plasma concentration vs time profiles were determined for fenbendazole and all of its metabolites. The total excretion of the drug and its metabolites in urine and feces was also measured for 6 days. A biliary cannula was inserted in 1 goat to study the excretion of fenbendazole and its metabolites into the bile. Fenbendazole was converted to its sulfoxide (oxfendazole), and the sulfone, primary amine, and p-hydroxylated metabolites. The active metabolite, oxfendazole, appeared in plasma, but only trace amounts were found in feces or urine. The major excretory metabolite was p-hydroxyfenbendazole.

Disposition of fenbendazole in cattle.

Fenbendazole (FBZ) was administered to cattle IV and orally in a crossover design. Plasma concentration vs time profiles were reported for FBZ and its major metabolites, the sulfoxide (oxfendazole) and the sulfone. The total excretion of FBZ and its metabolites in urine and feces was also measured for 6 days after administration. All known metabolites were identified in urine and feces except for fenbendazole amine. Neither this minor metabolite nor p-hydroxyfenbendazole (FBZ-OH) appeared in plasma. The major excretory product was FBZ-OH. After oral administration, only 44.6% of the dose was eliminated after 6 days, indicating a fairly high degree of sequestration, probably within the gastrointestinal tract.

Field trial of theophylline in cattle with respiratory tract disease.

A field trial was conducted to determine the efficacy of theophylline in relieving respiratory distress associated with bovine respiratory disease complex (shipping fever). Theophylline (as aminophylline capsules) was administered PO at a dosage of 28 mg/kg of body weight daily for 3 days to 20 calves with naturally acquired disease. Twenty similarly affected calves from the same group were given a placebo, and all calves were administered antibiotics concurrently. Respiratory rate and rectal temperature decreased and physical appearance improved in both groups of calves and was attributed to antibiotic administration or to natural remission of the disease. Five of the calves administered theophylline died; however, no calves administered the placebo died. Plasma theophylline concentration was greatly increased, compared with that determined in clinically normal calves in a pilot study. Bovine respiratory tract disease and/or concurrent antibiotic administration appear to cause such a rapid accumulation of lethal concentration of theophylline that its use should be restricted to hospitals capable of monitoring plasma theophylline concentration.

Therapeutic drug monitoring in veterinary medicine.

This article presents some of the more important principles and concepts of therapeutic drug monitoring and when it might be an appropriate diagnostic procedure in veterinary medicine.

Pharmacokinetics and metabolism of fenbendazole in channel catfish.

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t 1/2 alpha was 0.51 h, t 1/2 beta was 16.8 h, body clearance (C1B) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t 1/2 (abs) was 1.47 h, the t 1/2 beta was 20.1 h, and the tlag was 0.1 h. Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO2) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.

Metronidazole: a method for its determination in biological fluids and its disposition kinetics in the dog.

A method for the analytical determination of metronidazole concentrations in biological tissues was developed using high performance liquid chromatography. The procedure was employed to investigate the pharmacokinetics of metronidazole in dogs following intravenous and oral administration (44 mg/kg). The overall elimination rate constant beta was 0.0027 +/- 0.0005 min-1, the apparent specific volume of distribution (V'd) was 0.948 +/- 0.096 L/kg overall clearance (ClB) was 2.49 +/- 0.54 ml/kg/min and the rate constant for absorption Kab was 0.0456 +/- 0.0353 min-1. Oral bioavailability was high but variable (59%-100%). Implications of these data for chemotherapy of infections caused by anaerobic bacteria, trichomonads, and Giardia and for the sensitization of hypoxic neoplastic cells to radiotherapy are discussed.

Warfarin in the dog: pharmacokinetics as related to clinical response.

Warfarin was administered intravenously (i.v.) as a single dose of 1.5 mg/kg to healthy dogs and the pharmacokinetic parameters were investigated. Elimination could be described by a one-compartment open model. Values for the elimination half-life and apparent specific volume of distribution were 14.5 +/- 4.1 h and 0.22 +/- 0.04 litre/kg, respectively. Oral maintenance doses were calculated from the data collected following i.v. administration and administered every 12 h for a total of five doses after an initial i.v. loading dose of 1.5 mg/kg. Prothrombin times increased from a control value of 8.6 +/- 0.3 sec to 55.2 +/- 5.2 sec over a period of 96 h. Prothrombin time returned to control values by 62 h after withdrawal of the drug. We propose a dosage regimen of warfarin for anticoagulant therapy in the dog of 0.22 mg/kg to be given orally every 12 h. Prothrombin time should be monitored during therapy and the dose of warfarin modified according to the degree of suppression of coagulation factors desired.

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 of lidocaine and its active metabolites in dogs.

The pharmacokinetics of lidocaine in dogs were investigated following the intravenous and intramuscular administration of single doses of lidocaine hydrochloride. The mean elimination rate constant and the mean specific clearance determined for the intravenous portion of the study were 0.786 h-1 and 2.40 1/kg/h, respectively. Following intramuscular administration the mean absorption rate constant was 7.74 h-1. Absorption was nearly complete as the percentage of an intramuscular dose absorbed averaged 91.9%. Concentrations of two N-deethylated metabolites, determined following the administration of lidocaine suggest that monoethylglycinexylidide is eliminated rapidly while glycinexylidide is more slowly eliminated. The relative contribution of these metabolites to the therapeutic and toxic effects of lidocaine and the potential for glycinexylidide accumulation during lidocaine administration remain to be investigated.

Determination of the acute oral toxicity of theophylline in conscious dogs.

The purpose of this study was to define the minimum toxic concentrations and clinical signs of theophylline toxicity in healthy, conscious dogs. Five dogs were dosed orally in a five-way crossover design with sustained release theophylline (Theo-Dur tablets, Key Pharmaceuticals) at 0, 20, 40, 80, and 160 mg/kg. They were observed for a 9-h period for clinical signs of toxicity which had been previously determined in a pilot study. These signs included sinus tachycardia and central nervous stimulation (manifested as restlessness, excitement, or vomition). The Physiotel radiotransmitter telemetry system was used for the acquisition of the heart rate and ECG. Blood samples were obtained every hour for theophylline determination by high pressure liquid chromatography. The results showed that toxicity occurs at higher theophylline plasma concentrations in the dog (37-60 micrograms/ml) as compared to man (greater than 20 micrograms/ml) when dosed orally. Since current dosage regimens in dogs are designed to maintain trough-peak theophylline plasma concentrations between 10 and 20 micrograms/ml, the results indicate that the upper limit of this range appears to be safe in the dog.

Chronopharmacokinetics of theophylline in the cat.

Studies of theophylline pharmacokinetics in humans have shown that a higher peak concentration and area under the curve (AUC), with a shorter time to peak (tp) occur after a morning dose than after an evening dose. The purpose of this study was to determine whether theophylline pharmacokinetics in the cat were also influenced by the administration time of day. Theophylline was administered to six cats in a three-way cross-over study as a single dose of intravenous aminophylline and oral sustained-release theophylline (Slo-bid Gyrocaps and Theo-Dur Tablets), between 08.00-09.00 h (Phase I) and 20.00-21.00 h (Phase II). Subjects were maintained on a 12-h light (08.00-20.00 h): 12-h dark cycle. Similar to the human studies, the tp was shorter following the morning dose. Conversely, however, the peak plasma theophylline concentrations achieved in these cats following intravenous aminophylline and oral Slo-bid were significantly higher following the evening dose. The AUC obtained for Theo-Dur was also significantly greater following the evening dose. No single pharmacokinetic parameter could account for the higher plasma concentrations achieved following the evening dose.

Determination of lidocaine concentrations producing therapeutic and toxic effects in dogs.

Lidocaine was infused at a fixed zero-order rate to eight healthy mongrel dogs until tonic extension (n = 5) and cortical seizures (n = 7) were produced. Lidocaine concentrations determined at 5-min intervals were used to calculate concentrations at which these effects occurred. The tonic extension phase occurred at a mean lidocaine concentration of 8.21 +/- 1.69 micrograms/ml. After a 1-month rest period, the same dogs were anaesthetized and ventricular tachycardia was produced by administering ouabain. Lidocaine was again infused at a fixed zero-order rate until all beats of ventricular origin were abolished. This occurred at a mean lidocaine concentration of 6.25 +/- 1.49 micrograms/ml.

Pharmacokinetic studies of theophylline in dogs.

The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life (t1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution (V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life (t1/2ab) was 0.4 h. Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.

Pharmacokinetics of chloramphenicol in non-lactating cattle.

The pharmacokinetics and bioavailability of a formulation of chloramphenicol base in propylene glycol were determined following administration of single intravenous (i.v.) and subcutaneous (s.c.) 50 mg/kg doses of chloramphenicol to six non-lactating Holstein cows. Mean serum concentrations of chloramphenicol following i.v. administration of 50 mg/kg declined rapidly from a peak of greater than 100 micrograms/ml to 6.9 micrograms/ml at 12 h after administration. Serum concentrations were not detectable at 24 h after administration. The curve of serum concentrations vs time was characteristic of a two-compartment open model. Mean i.v. data gave a biological half-life of 4.3 h and a volume of distribution of the central compartment of 0.44 l/kg. Serum concentrations of chloramphenicol following s.c. administration of 50 mg/kg rose slowly to a broad peak near 20 micrograms/ml from 3 to 8 h after administration and then declined. These data were also analysed according to a two-compartment open model. The biological half-life was 4.2 h and the volume of distribution of the central compartment was 0.50 l/kg. Significant adverse reactions, including acute collapse, intravascular haemolysis and haemoglobinuria, were observed in cows when dosed i.v. Cows dosed s.c. exhibited local reactions at injection sites. The disadvantages of administration of 50 mg/kg doses of chloramphenicol base in propylene glycol appear to be significant and may outweight the potential advantages of parenteral use of the drug as presently formulated.

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.