Feasibility of interspecies extrapolation in determining the bioequivalence of animal products intended for intramuscular administration.

To examine the validity of extrapolating parenteral product bioequivalence determinations across target animal species, the relative bioavailability of two injectable formulations of ampicillin trihydrate (PolyflexR, a water-based suspension, and Ampi-kel 10R, an oil-based suspension) was examined in calves, sheep and swine. Employing products recognized to be bioinequivalent provided an opportunity to explore potential species-by-formulation interactions. As compared with PolyflexR, Ampi-kel 10R exhibited lower area under the curve (AUC) estimates but higher peak concentrations in all target animal species. Nevertheless, marked interspecies differences were noted in the width and bounds of the confidence intervals about the differences in treatment means. Potential physiological and physico-chemical reasons for these findings are discussed.

Determination of oxytetracycline in bovine kidney and medicated milk replacer by liquid chromatography.

Improvements and optimization of AOAC INTERNATIONAL Official Method 995.09 for the detection of oxytetracycline in bovine kidney at the new U.S. tolerance of 12 ppm are reported. Recoveries from kidney fortified at 4 concentrations over the range of 3-40 ppm averaged 84-98%. Results from the kidney of a calf fed medicated milk replacer containing oxytetracycline are also reported. Additionally, adaptation of this method to the detection of oxytetracycline in medicated milk replacer is discussed.

Depletion of gentamicin in the milk of Holstein cows after single and repeated intramammary and parenteral treatments.

Twenty-four healthy Holstein cows, 2.72 +/- 0.64 (mean +/- SD) years old, weighing 603.96 +/- 73.22 kg (mean +/- SD), and representing various levels of milk production, were used to determine the depletion of gentamicin (GT) in milk. The cows had not received antibiotics or other drugs that could interfere with study for at least 60 days before the beginning of the investigation. The cows were divided into six groups (n = 4) and treated with single (treatments A, B and C) or repeated (treatments D, E and F) doses of GT. Cows were acclimated for 7 days before administration of GT and milked twice a day at 12-h intervals (06.00 hours, 18.00 hours) throughout the duration of the study. Control milk samples were obtained after the arrival of the cows and assayed to establish their GT free status. On day 1 of each treatment, a baseline milk sample was collected from the milk produced (06.00 hours) by each cow. A single dose of GT was administered intramammarily (A, i.m.m. left front quarter, 500 mg), intravenously (B, i.v., 5 mg/kg body weight) or intramuscularly (C, i.m., 5 mg/kg body weight). Cows in treatments D (i.m.m., 500 mg), E (i.v., 5 mg/kg body weight) and F (simultaneous i.m.m. 500 mg plus i.v. 5 mg/kg body weight) were treated twice a day for 5 consecutive days just after the morning and evening milkings. Milk samples from individual cows were collected every day after each milking during and after dosing until GT concentration in the milk was below the safe level of < or = 30 ng/mL. The concentration of GT in milk was determined by a high-performance liquid chromatographic procedure. Depletion of GT to a concentration < or = 30 ng/mL occurred at the seventh (84 h), third (36 h), third (36 h), eleventh (132 h) third (36 h) and nineteenth (228 h) post-dosing milking, for cows in treatments A, B, C, D, E and F respectively. The highest mean +/- SEM) concentrations of GT were 14 710 +/- 1213.89, 167.87 +/- 46.94 and 91.62 +/- 14.55 ng/mL measured in the first milking post dosing (12 h) for cows in treatment A, B and C respectively; for cows in treatments D, E and F, during the dosing period, they were 14067.50 +/- 2989.09, 446.07 +/- 100.92, and 22900 +/- 2843.66 ng/mL and occurred at the seventh, third and eighth milking respectively. Because GT is not approved for use in dairy cattle and because of the long depletion time associated with some possible treatments, illegal and extra-label use is likely to cause residues in milk.

Disposition and bioavailability of neomycin in Holstein calves.

The disposition and absorption kinetics of neomycin were studied in healthy ruminating dairy calves (n = 6), approximately 3-months-old. The calves were treated with single intravenous (i.v.) (12 mg/kg), intramuscular (i.m.) (24 mg/kg), oral (p.o.) (96 mg/kg) and repeated p.o. (96 mg/kg, b.i.d., 15 1/2 days) doses of neomycin. A 3-week rest period was allowed between treatments A and B, and B and C. Baseline and serial venous blood samples were collected from each calf. Plasma concentrations of neomycin were determined by a high performance liquid chromatography procedure. The resulting data were evaluated by using compartmental pharmacokinetic models and nonlinear least squares regression analysis. The mean of some selected parameters were t1/2 lambda 3 7.48 +/- 2.02 h, Clt = 0.25 +/- 0.04 L/h/kg, Vd(ss) = 1.17 +/- 0.23 L/kg, and MRT = 4.63 +/- 0.87 h for the i.v. data and t1/2 = 11.5 +/- 3.8 h, MRTabs = 0.960 +/- 1.001 h, F = 127 +/- 35.2%, and Clt/F = 0.199 +/- 0.047 L/h/kg for the i.m. data, respectively. Only one calf absorbed neomycin to any significant degree (F = 0.0042) after a single p.o. dose. Selected mean parameters determined after repeated oral dosing were: F = 0.45 +/- 0.45%, Cmax = 0.26 +/- 0.37 microgram/ml, and tmax = 2.6 +/- 2.9 h. Terminal half-lives determined for the i.v. and i.m. treatments were considerably longer than those reported previously in the literature.

Pharmacokinetics of L-thyroxine after its oral administration in dogs.

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered L-thyroxine. The dogs were treated with 44, 22, and 11 micrograms of L-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (Css) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of ANOVA. Concentration at steady state was highest for dogs of the 44-micrograms/kg of body weight once-daily group and was lowest for dogs of the group given 11 micrograms/kg in 2 daily doses. Single daily administration resulted in higher Css, except at the 22-micrograms/kg/d dosage. Clearance was faster for the 22- and 44-micrograms/kg/d dosages than for the 11-micrograms/kg/d dosage. The half-life (t1/2) and mean residence time (MRT) also were shorter for the 44-micrograms/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs' metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of phenobarbital in horses after single and repeated oral administration of the drug.

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 +/- 4.7 and 11.2 +/- 2.3 hours, volume of distribution = 0.960 +/- 0.060 and 0.914 +/- 0.119 L/kg, and clearance = 28.2 +/- 5.1 and 57.3 +/- 9.6 ml/h/kg, respectively. Results indicated that significant (P less than 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for gamma-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required.(ABSTRACT TRUNCATED AT 250 WORDS)

Ototoxic potential of gentamicin in ponies.

Ototoxicosis was evaluated in 6 healthy ponies given 5 mg of gentamicin/kg of body weight, q 8 h, IM. Ponies 1, 2, and 3 were dosed for 7 days and ponies 4, 5, and 6 were dosed for 14 days. Serum peak and trough concentrations of gentamicin were measured by radioimmunoassay at regular intervals. Brain stem auditory-evoked responses were recorded every 5 days up to 60 days after the first dose to monitor auditory function. Although serum gentamicin concentrations were within or above the accepted clinical therapeutic range, loss of auditory function was not observed at the frequency range (1 to 4 kHz) tested. Serum chemical values remained within the accepted clinical range and no evidence of nephrotoxicosis was observed. Seemingly, gentamicin given IM to healthy ponies was safe and had minimal risk of side effects.

Pharmacokinetics of single doses of digoxin administered intravenously to ducks, roosters, and turkeys.

A single dose of digoxin was injected, IV, into 5 mature male turkeys (0.066 mg/kg of body weight), 8 male ducks (0.066 mg/kg), and 6 roosters (0.33 mg/kg). Twenty-three serial venous blood samples were collected before (baseline) and after the administration of digoxin to turkeys, ducks, and roosters. Plasma concentrations of digoxin were determined in duplicate by a radioimmunoassay that was validated for avian species. The plasma concentrations were best fitted by a 3 (turkeys, ducks)- and 2 (roosters)-compartment open model, with first-order elimination from the central compartment. Significant (P less than 0.05) kinetic differences were determined among species. Mean half-life (t1/2) for ducks, roosters, and turkeys were 8.30 +/- 2.70 (mean +/- SD), 6.67 +/- 3.50, and 23.7 +/- 4.8 hours, respectively. The volume of distribution at steady state (Vss) was 14.7 +/- 2.9, 3.13 +/- 0.49, and 2.27 +/- 0.36 L/kg, and total body clearance (CL) of drug was 1.54 +/- 0.43, 0.461 +/- 0.187, and 0.136 +/- 0.022 L/h/kg for ducks, roosters, and turkeys, respectively. The mean residence time was 10.3 +/- 3.9, 8.37 +/- 4.97, and 16.8 +/- 2.2 hours, respectively. Volume of distribution at steady state and CL in ducks were several fold higher than that in turkeys. The terminal half-life of digoxin determined for ducks and roosters in this study was considerably shorter than those previously reported for several mammalian species.

Pharmacokinetics of single-dose intravenous or intramuscular administration of gentamicin in roosters.

Healthy mature roosters (n = 10) were given gentamicin (5 mg/kg of body weight, IV) and, 30 days later, another dose IM. Serum concentrations of gentamicin were determined over 60 hours after each drug dosing, using a radioimmunoassay. Using nonlinear least-square regression methods, the combined data of IV and IM treatments were best fitted by a 2-compartment open model. The mean distribution phase half-life was 0.203 +/- 0.075 hours (mean +/- SD) and the terminal half-life was 3.38 +/- 0.62 hours. The volume of the central compartment was 0.0993 +/- 0.0097 L/kg, volume of distribution at steady state was 0.209 +/- 0.013 L/kg, and the total body clearance was 46.5 +/- 7.9 ml/h/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.281 +/- 0.081 hours. The extent of IM absorption was 95 +/- 18%. Maximal serum concentration of 20.68 +/- 2.10 micrograms/ml was detected at 0.62 +/- 0.18 hours after the dose. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 4 mg/kg, q 12 h, and 1.5 mg/kg, q 8 h, would provide average steady-state serum concentrations of 6.82 and 3.83 micrograms/ml, with minimal steady-state serum concentrations of 1.54 and 1.50 micrograms/ml and maximal steady-state serum concentrations of 18.34 and 7.70 micrograms/ml, respectively.

Pharmacokinetics of phenobarbital in dogs given multiple doses.

Studies were conducted to examine the temporal changes in phenobarbital pharmacokinetics during chronic dosing in dogs. Ten dogs were allotted into 2 groups, administered a single oral dose, rested for 35 days, and then given the drug for 90 consecutive days. After single administration of 5.5 mg/kg of body weight or 15 mg/kg, the total body clearance (Clt/F) was 5.58 +/- 1.89 ml/h/kg and 7.28 +/- 1.07 ml/h/kg, respectively. The half-lives (t1/2) for the 2 groups were 88.7 +/- 19.6 hours for the 5.5-mg/kg dose and 99.6 +/- 22.6 hours for the 15-mg/kg dose. Significant differences in Clt/F or t1/2 were not observed between the 2 groups. Multiple-dosing regimens (5.5 mg/kg/day or 11 mg/kg/day) were initiated in the same dogs for 90 days. The Clt/F was significantly (P less than 0.05) greater on days 30, 60, and 90 than the single dose for both groups. After the last dose on day 90, several blood samples were obtained to determine phenobarbital t1/2. On day 90, the t1/2 was significantly (P less than 0.05) shorter and the Clt/F was significantly greater than single-dose values. The Clt/F and t1/2 were 10.2 +/- 1.7 ml/h/kg and 47.3 +/- 10.7 hours for the group given the low dose and 15.6 +/- 2.5 ml/h/kg and 31.1 +/- 4.4 hours for the group given the high dose, respectively. Both Clt/F and t1/2 were significantly (P less than 0.05) different between the 2 groups on day 90.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of single doses of gentamicin given intravenously and intramuscularly to turkeys.

The disposition and absorption kinetics of gentamicin were studied in healthy, mature male and female turkeys (n = 10). Single doses of gentamicin (5 mg/kg) were injected either i.v. or i.m. with a 30-day rest period between each treatment. Baseline and serial venous blood samples (n = 17) were collected from each turkey. Serum concentrations of gentamicin were determined in duplicate for 24 h after each treatment, using radio-immunoassay. Using nonlinear least-square regression methods, the combined data of the i.v. and i.m. treatments were best described by a two-compartment open model. Kinetic analysis of the data after a single i.v. dose provided the following mean values: t1/2 alpha = 0.170 +/- 0.093 h, t1/2 beta = 2.57 +/- 0.79 h, MRT = 3.62 +/- 0.96 h, Vc = 0.090 +/- 0.017 l/kg, Vd(ss) = 0.172 +/- 0.024 l/kg, Vd(area) = 0.190 +/- 0.030 l/kg, and Clt = 49.8 +/- 9.8 ml/h/kg. After a single i.m. dose, the following mean values were determined: MRT = 5.10 +/- 1.73 h, t1/2abs = 0.74 +/- 0.66 h, tlag = 0.07 +/- 0.19 h, Clt/F = 50.7 +/- 12.5 ml/h/kg, Vd(area)/F = 0.193 +/- 0.044 l/kg, and F = 102 +/- 21%. Kinetic calculations made with the single i.m. data predicted that an i.m. injection of gentamicin at the dosage rate of 3 mg/kg q. every 12 h would provide average steady state serum concentrations of 4.93 micrograms/ml.

Effects of fenbendazole administration on hematology, clinical chemistries and selected hormones in the white Pekin duck.

The effects of single i.v. and p.o. doses (5 mg/kg) of fenbendazole, were evaluated on thyroxine, tri-iodothyronine, corticosterone, hematology, clinical chemistries, and serum proteins in 10 white Pekin ducks. Fenbendazole was administered i.v. (n = 5) as a 3% dimethyl sulfoxide solution and p.o. (n = 5) as a 10% commercial suspension. Serum enzyme concentrations, total protein and protein fractions, glucose, cholesterol, uric acid, sodium, and potassium were unchanged from baseline values. Serum triglycerides decreased consistently in the i.v.-treated group but remained unchanged in the p.o.-treated group. Serum chloride was consistently elevated above baseline values for both i.v.- and p.o.-treated ducks, while inorganic phosphate was consistently decreased only in the i.v.-treated group. Hemoglobin and hematocrit values generally were below baseline values. Leukocyte values varied considerably and were not significantly different from baseline values. Serum thyroxine and tri-iodothyronine values in both the i.v.- and p.o.-treated groups were not changed significantly from baseline values. Serum corticosterone values were not changed in the i.v.-treated groups but they were decreased at various times in the p.o.-treated group. Although there were some sporadic significant changes in the parameters measured versus baseline values all values remained within the physiologic limits for ducks. The safety of fenbendazole has been previously demonstrated for several species.

Erythrocyte distribution in ducks.

A study on erythrocyte distribution was performed on 10 healthy, nonstressed adult white Pekin ducks. Results indicated 2 populations of erythrocytes, with average mean corpuscular volumes of 128.37 fl/cell and 308.50 fl/cell. Variations in erythrogram patterns were evident over time, when comparing specimens from different ducks or the same duck. There were 5 patterns of cell number/volume distribution observed between the 2 cell populations when all ducks were studied. Females had a greater change than did males when population density and volume percentage comparisons were made on erythrocyte compartments.

Comparative albumin determinations in ducks, chickens, and turkeys by electrophoretic and dye-binding methods.

Serum total protein, albumin, and globulin concentrations in male ducks, turkeys, and chickens were compared, using electrophoretic and dye-binding methods, as well as using a bovine and chicken albumin standard. When a chicken standard was used for determination of albumin and globulin concentrations by automated methods, results were more comparable with results of electrophoresis than were those when a bovine standard was used.

Techniques for blood sampling in avian species.

In avian species' common sites for blood sampling include the basilic, jugular, and superficial plantar metatarsal veins, heart and occipital sinus. The lateral thoracic vein is also used in the turkey. The sites with the least trauma to the animal are the basilic, superficial plantar metatarsal, and lateral thoracic veins from which adequate volumes of blood can be obtained. Heart puncture and occipital sinus sampling procedures are expedient and large volumes of blood can be obtained however these sites are the most traumatic. The superficial plantar metatarsal vein was the site for best repeat sampling in the duck and the chicken and the basilic in the turkey.

A pharmacokinetic study of phenobarbital in mature horses after oral dosing.

The pharmacokinetics of phenobarbital were determined in six mature horses after a single oral dose. Horses were administered a 5.5 mg/kg of body weight oral dose of phenobarbital tablets. Based on the combined evaluation of i.v. and oral results, phenobarbital displayed two-compartment pharmacokinetics in the horse with a terminal half-life of 19.0 +/- 4.4 (mean +/- SD) h. This half-life is considerably shorter than those reported for dogs and humans. The steady-state volume of distribution (Vdss/F) and the total body clearance (Clt/F) of phenobarbital were 0.753 +/- 0.115 l/kg and 27.9 +/- 9.2 ml/h/kg, respectively. The average extent of oral absorption was 101% with a range of 76 to 124% among the six horses. Examination of the absorption kinetics demonstrated a biphasic absorption process in four horses with a rapid absorption followed by a slower absorption phase. The mean residence time (MRT) was 36.9 +/- 4.1 h and the mean residence time for oral absorption (MRTabs) was 11.3 h. Based on the results of the present study, an oral dosing regimen of 11 mg/kg of body weight every 24 h can be recommended.

Baseline hematologic, endocrine, and clinical chemistry values in ducks and roosters.

Venous blood samples were collected at 3-day intervals for a total of six samples from each of five adult male pekin ducks and five adult Ross roosters. Twenty biochemical, six hematologic, and three endocrine determinations were performed on each blood or serum sample collected. The data obtained provide reference values for future studies of avian species and illustrate the utility of an automated clinical chemistry analyzer in assessing multiple serum biochemistry values in small sample volumes obtained from birds.

Pharmacokinetics and interactions of digoxin with phenobarbital in dogs.

In one experiment, 5 dogs were administered digoxin (0.022 mg/kg of body weight, IV), were rested for 2 weeks, were then given phenobarbital (13.2 mg/kg orally) for 14 days, and then were given digoxin again (0.022 mg/kg, IV). Comparing prephenobarbital (control) digoxin half-lives of 42.4 +/- 8.8 hours and postphenobarbital digoxin half-lives of 18.0 +/- 2.2 hours, the half-life was significantly (P less than 0.05) decreased after phenobarbital administration. Clearance was increased by 84%, and the volume of distribution given was decreased by 34%. In a second experiment, 5 dogs were given digoxin (0.022 mg/kg, orally) daily for 11 days, and the digoxin kinetics were evaluated after the last dosing. The dogs were then rested and given phenobarbital (13.2 mg/kg, orally) once daily for 14 days and digoxin (0.022 mg/kg) once daily for 11 days, and the pharmacokinetics of digoxin was determined on the last day of dosing. Significant differences in steady-state serum concentrations and the pharmacokinetics of digoxin were not found between the control and phenobarbital phases of the experiment. Mean (+/- SD) half-lives of digoxin were 29.0 +/- 7.2 hours before phenobarbital treatment (control) and were 34.8 +/- 7.2 hours after phenobarbital treatment. In comparing results of the single-dose experiment vs the oral multiple-dose experiment, dogs had shorter half-lives for digoxin after multiple dosing. Therefore, if phenobarbital and digoxin are to be chronically coadministered orally, an adjustment in the digoxin dose is not necessary.