Pharmacokinetic parameters for single- and multi-dose regimens for subcutaneous administration of a high-dose ceftiofur crystalline-free acid to neonatal foals.

The objective of this study was to determine the pharmacokinetics of single- and multi-dose ceftiofur crystalline-free acid (CCFA) administered subcutaneously at a dose of 13.2 mg/kg to 12 neonatal foals 1-3 days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48-h intervals. Blood samples were collected at pre-determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high-performance liquid chromatography. Following single-dose administration of CCFA, the mean ± standard deviation maximum observed plasma concentration was 3.1 ± 0.6 µg/mL and observed time to maximal plasma concentration was 14.0 ± 4.9 h. Following multi-dose administration of CCFA, the mean ±standard deviation times above CFAE concentrations of ≥0.5 µg/mL and ≥2.0 µg/mL were 192.95 ± 15.86 h and 78.80 ± 15.31 h, respectively. The mean ± standard deviation area under the concentration vs time curve (AUC0→∝ ) was 246.2 ± 30.7 h × µg/mL and 172.7 ± 27.14 h × µg/mL following single- and multi-dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2 mg/kg in neonatal foals was clinically well- tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi-dose administration of four doses at dosing interval of 48 h between treatments maintains appropriate therapeutic concentrations in neonatal foals.

Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus).

Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2 ppm, respectively, with a 6-hr feed withdrawal. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young pheasants and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, two large game bird farms fed fendbendazole at 100 ppm for 7 days and collected data on hatching percentage of pheasant eggs before and after treatment. Reproductive performance in hen pheasants was not adversely affected.

Pharmacokinetics of tulathromycin in plasma and milk samples after a single subcutaneous injection in lactating goats (Capra hircus).

Eight adult female dairy goats received one subcutaneous administration of tulathromycin at a dosage of 2.5 mg/kg body weight. Blood and milk samples were assayed for tulathromycin and the common fragment of tulathromycin, respectively, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of tulathromycin was analyzed by a noncompartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of tulathromycin were as follows: C(max) (121.54 ± 19.01 ng/mL); T(max) (12 ± 12-24 h); area under the curve AUC(0→∞) (8324.54 ± 1706.56 ng·h/mL); terminal-phase rate constant λz (0.01 ± 0.002 h⁻¹); and terminal-phase rate constant half-life t1/2λz (67.20 h; harmonic). Mean milk pharmacokinetic parameters (±SD) following 45 days of sampling were as follows: Cmax (1594 ± 379.23 ng/mL); Tmax (12 ± 12-36 h); AUC(0→∞) (72,250.51 ± 18,909.57 ng·h/mL); λz (0.005 ± 0.001 h⁻¹); and t(1/2λz) (155.28 h; harmonic). All goats had injection-site reactions that diminished in size over time. The conclusions from this study were that tulathromycin residues are detectable in milk samples from adult goats for at least 45 days following subcutaneous administration, this therapeutic option should be reserved for cases where other treatment options have failed, and goat milk should be withheld from the human food chain for at least 45 days following tulathromycin administration.

Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis.

The objective of this study was to determine the pharmacokinetics of CCFA in mares with placentitis and evaluate the disposition of the drug in fetal fluids, fetal membranes, colostrum, and serum of foals. A secondary objective was to obtain pilot data regarding the efficacy of CCFA for improving foal survival in mares with placentitis. Twelve pregnant pony mares were enrolled in the study, inoculated with Streptococcus zooepidemicus, intracervically and assigned to one of three groups: CEFT (n = 3; administered CCFA only; 6.6 mg/kg, i.m., q96h); COMBO (n = 6; administered combination therapy of CCFA, altrenogest, and pentoxifylline); UNTREAT (n = 3, no treatment). Treatment was initiated at the onset of clinical signs. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur metabolites, were measured using high-performance liquid chromatography. Maximum and minimum serum concentrations of DCA at steady state in treated mares were 2.40±0.40 µg/mL and 1.06±0.29 µg/mL, respectively. Concentration of DCA in colostrum was 1.51±0.60 µg/mL. DCA concentrations in placenta and fetal tissues were very low (median = 0.03 µg/mL) and below the minimum inhibitory concentration of relevant pathogens. DCA was not detected in amniotic fluid or foal serum. Treatment did not appear to improve foal survival (CEFT: 0/3; COMBO: 2/6; UNTREAT: 2/3). Bacteria were recovered from the uterus of most mares postpartum and from blood cultures of most foals regardless of treatment.

Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos).

Six adult male alpacas received one subcutaneous administration of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. After a washout period, the same alpacas received three subcutaneous doses of 6.6 mg/kg CCFA at 5-day intervals. Blood samples collected from the jugular vein before and at multiple time points after each CCFA administration were assayed for ceftiofur- and desfuroylceftiofur-related metabolite concentrations using high-performance liquid chromatography. Pharmacokinetic disposition of CCFA was analyzed by a noncompartmental approach. Mean pharmacokinetic parameters (± SD) following single-dose administration of CCFA were Cmax (2.7 ± 0.9 µg/mL); Tmax (36 ± 0 h); area under the curve AUC0→∞ (199.2 ± 42.1 µg·h/mL); terminal phase rate constant λz (0.02 ± 0.003/h); and terminal phase rate constant half-life t1/2λz (44.7 h; harmonic). Mean terminal pharmacokinetic parameters (±SD) following three administrations of CCFA were Cmax (2.0 ± 0.4 µg/mL); Tmax (17.3 ± 16.3 h); AUC0→∞ (216.8 ± 84.5 µg·h/mL); λz (0.01 ± 0.003/h); and t1/2λz (65.9 h; harmonic). The terminal phase rate constant and the Tmax were significantly different between single and multiple administrations. Local reactions were noted in two alpacas following multiple CCFA administrations.

Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus).

Tulathromycin is a macrolide antimicrobial labeled for treatment of bacterial pneumonia in cattle and swine. The purpose of the present research was to evaluate tissue concentrations of tulathromycin in the caprine species. A tandem mass spectrometry regulatory analytical method that detects the common fragment of tulathromycin in cattle and swine was validated with goat tissues. The method was used to study tulathromycin depletion in goat tissues (liver, kidney, muscle, fat, injection site, and lung) over time. In two different studies, six juvenile and 25 market-age goats received a single injection of 2.5 mg/kg of tulathromycin subcutaneously; in a third study, 18 juvenile goats were treated with 2.5, 7.5, or 12.5 mg/kg tulathromycin weekly with three subcutaneous injections. Mean tulathromycin tissue concentrations were highest at injection site samples in all studies and all doses. Lung tissue concentrations were greatest at day 5 in market-age goats while in the multi-dose animals concentrations demonstrated dose-dependent increases. Concentrations were below limit of quantification in injection site and lung by day 18 and in liver, kidney, muscle, and fat at all time points. This study demonstrated that tissue levels in goats are very similar to those seen in swine and cattle.

Pharmacokinetics of tulathromycin after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus).

Tulathromycin, a novel triamilide in the macrolide class, is labeled for treatment of bacterial pneumonia in cattle and swine. This manuscript evaluates pharmacokinetics of tulathromycin in goats. In two different studies, six juvenile and ten market-age goats received a single injection of 2.5 mg/kg of tulathromycin subcutaneously; in a third study, 18 juvenile goats were treated with 2.5, 7.5, or 12.5 mg/kg tulathromycin weekly with three subcutaneous injections. Pharmacokinetic parameters estimated from the plasma concentrations from single injections were similar between the two groups of goats and to previously reported parameters in cattle and swine. Mean terminal half-lives were 59.1 ± 7.6 and 61.2 ± 8.7 h for juvenile and market-age goats, respectively. In the multi-dose study, pharmacokinetic parameters estimated from plasma concentrations demonstrated significant differences at P < 0.05 among repeated injections but not among doses. Overall, pharmacokinetic parameters in goats are similar to those reported in cattle and swine, and tulathromycin may prove a useful drug for treating respiratory disease in goats.

Pharmacokinetics of ceftiofur sodium and ceftiofur crystalline free acid in neonatal foals.

Ceftiofur, a third generation cephalosporin, demonstrates in vitro efficacy against microorganisms isolated from septicemic neonatal foals. This pharmacokinetic study evaluated the intravenous and subcutaneous administration of ceftiofur sodium (5 mg/kg body weight; n = 6 per group) and subcutaneous administration of ceftiofur crystalline free acid (6.6 mg/kg body weight; n = 6) in healthy foals. Plasma ceftiofur- and desfuroylceftiofur-related metabolite concentrations were measured using high performance liquid chromatography following drug administration. Mean (±SD) noncompartmental pharmacokinetic parameters for i.v. and s.c. ceftiofur sodium were: AUC(0→∝) (86.4 ± 8.5 and 91 ± 22 h·µg/mL for i.v. and s.c., respectively), terminal elimination half-life (5.82 ± 1.00 and 5.55 ± 0.81 h for i.v. and s.c., respectively), C(max(obs)) (13 ± 1.9 µg/mL s.c.), T(max(obs)) (0.75 ± 0.4 h for s.c.). Mean (± SD) noncompartmental pharmacokinetic parameters for s.c. ceftiofur crystalline free acid were: AUC(0→∝) (139.53 ± 22.63 h·µg/mL), terminal elimination half-life (39.7 ± 14.7), C(max(obs)) (2.52 ± 0.35 µg/mL) and t(max(obs)) (11.33 ± 1.63 h). No adverse effects attributed to drug administration were observed in any foal. Ceftiofur- and desfuroylceftiofur-related metabolites reached sufficient plasma concentrations to effectively treat common bacterial pathogens isolated from septicemic foals.

Progesterone milk residues in goats treated with CIDR-G(®) inserts.

Progesterone (P4)-impregnated intravaginal controlled internal drug-releasing devices (CIDRs) have been used worldwide for estrus synchronization in ruminants. CIDRs serve to place all treated animals in the luteal phase of the estrous cycle. The objectives of this study were to compare P4 concentrations in milk from normal reproductively cycling, CIDR-treated, and pregnant goats. CIDRs were placed in treatment goats on day 0 and removed on day 19. Milk was collected daily from day 0 to day 21 from control and CIDR-treated goats and for 5 consecutive days between 40 and 60 days of gestation from pregnant does. Milk P4 was plotted against time (in days) for each individual, and the area under the curve (AUC) was calculated as an estimate of total milk P4. The AUC(day 0-21) for control and CIDR-treated goats were 29.5 ± 11.9 and 33.7 ± 6.6 d·ng/mL, respectively (P = 0.77). The highest single-day and highest 5-day average P4 values for each animal were also compared among groups. Single-day peak P4 levels were 4.8 ± 1.5, 4.0 ± 1.0, and 6.0 ± 0.4 ng/mL for control, CIDR-treated, and pregnant goats (P = 0.42). The highest 5-day average P4 concentrations were 3.6 ± 1.3, 2.9 ± 1.8, and 4.2 ± 0.3 for control, CIDR-treated, and pregnant goats (P = 0.56). The results of this study show that intravaginal P4 CIDR devices inserted for 19 days in healthy goats resulted in milk P4 levels similar to or less than those endogenously produced during diestrus or pregnancy.

Florfenicol residues in three species of fish after 10-day oral dosing in feed.

Nile tilapia Oreochromis niloticus, walleye Sander vitreus, and hybrid striped bass (female white bass Morone chrysops x male striped bass M. saxatilis) were medicated with florfenicol (AQUAFLOR type A medicated article; Schering-Plough Animal Health, Summit, New Jersey) via a medicated ration of 10 mg florfenicol x kg fish body weight(-1) d(-1) for 10 d to compare the elimination kinetics of the test article. This study was part of a larger effort in support of a species grouping concept that could contribute to the regulatory approval process for therapeutic compounds for cultured fishes. The trials in this study were conducted at the ideal water temperature for each species and at the temperature 5 degrees C lower than the ideal. The test temperatures were 30 degrees C and 25 degrees C for Nile tilapia, 25 degrees C and 20 degrees C for both walleyes and hybrid striped bass. In all cases, the elimination kinetics of florfenicol were more rapid at higher temperatures. The time to reach the tolerance of 1 microg/g in muscle-skin, as set by the U.S. Food and Drug Administration for channel catfish Ictalurus punctatus and salmonids, ranged from 6.1 to 4.1 d for Nile tilapia, from 12.6 to 9.7 d for walleyes, and from 2.6 to 0.7 d for hybrid striped bass at temperatures between 20 degrees C and 30 degrees C.

Florfenicol residues in Nile tilapia after 10-d oral dosing in feed: effect of fish size.

Nile tilapia Oreochromis niloticus were medicated with florfenicol (AQUAFLOR type A medicated article; Schering-Plough Animal Health, Summit, New Jersey) via a medicated ration at 15 mg florfenicol x kg fish body weight(-1) d(-1) for 10 d to compare the elimination kinetics of the test article in different size fish held at 25 degrees C. The groups of fish used in the study had mean weights of approximately 100, 250, and 500 g. In each trial, the fish were provided the medicated ration and 15 fish were processed at each of seven time points postfeeding for determination of the florfenicol concentration in serum and the florfenicol residue in the edible portion (composite muscle and skin). There was a trend toward shorter half-lives of elimination in the smaller fish. The elimination times in muscle-skin (times to reach the established tolerance concentration for channel catfish Ictalurus punctatus and salmonids of 1.0 microg florfenicol residue/g) and half-lives were 9.2 and 1.2 d (100 g), 8.6 and 1.7 d (250 g), and 12.7 and 2.2 d (500 g), respectively.

A PBPK model for midazolam in four avian species.

A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.

Plasma pharmacokinetics of midazolam in chickens, turkeys, pheasants and bobwhite quail.

In vivo plasma pharmacokinetics of midazolam hydrochloride (5 mg/kg i.v.) were determined in commercially raised broiler chickens, turkeys, ring-necked pheasants and bobwhite quail. Pharmacokinetic profiles of midazolam were similar for all four species, especially with regard to the area under the plasma drug concentration-time curve. Estimates of the half-life of elimination of midazolam were 0.42, 1.45, 1.90, and 9.71 h for turkeys, chickens, bobwhite quail, and pheasant, respectively. This was similar to the major metabolite (1-hydroxymidazolam). Elimination half-lives for 1-hydroxymidazolam were 1.35, 1.86, 1.97, and 13.97 h for turkey, chicken, bobwhite quail and pheasant, respectively. Elimination half-lives for 4-hydroxymidazolam were 0.76, 1.23, 2.85, and 13.82 h for chicken, turkey, pheasant, and bobwhite quail, respectively. In addition to traditional pharmacokinetic approaches to parameter estimation, a bootstrapping technique was employed to attempt to achieve more realistic approximations of the concentrations at later time-points.

Investigation of Japanese quail (Coturnix japonica) as a pharmacokinetic model for cockatiels (Nymphicus hollandicus) and Poicephalus parrots via comparison of the pharmacokinetics of a single intravenous injection of oxytetracycline hydrochloride.

The purpose of this study was to determine whether Japanese quail (Coturnix japonica) would serve as a pharmacokinetic animal model for two small companion parrots: cockatiels (Nymphicus hollandicus) and Poicephalus parrots. Oxytetracycline (OTC) was the pharmacologic agent chosen for this study as it is eliminated primarily by renal glomerular filtration and undergoes minimal metabolism. A single intravenous injection of 20 mg/kg oxytetracycline hydrochloride was administered to the three study groups and blood samples were obtained at 5, 10, 15, and 30 min post-OTC injection as well as 1, 2, 4, 8, 12 and 24 h post-OTC injection. Quantification of plasma OTC was accomplished using a standardized microbial inhibition assay. Naïve-pooled data (NPD) analysis of the plasma concentration-time profile of OTC best fit a two-compartment open model for all three avian species. Noncompartmental analysis of the mean data yielded the following parameters for quail, cockatiels and Poicephalus parrots respectively: lambda(z) = 3.14, 4.57, 3.71 h; AUC = 38.9, 42.7, 49.6 microg x h/mL; and Cl = 514, 468, 403 mL/h/kg. Based on the similarity of these pharmacokinetic parameters, it appears that quail could be used as a model species to predict the appropriate OTC dosing regimen for small psittacine birds. A bootstrap procedure was also applied to these sparse data sets for both compartmental and noncompartmental analysis. The bootstrap procedure allowed for the calculation of variability of parameters; however, the estimates of the parameters were very similar to those calculated using the NPD and the data mean values.

Intravenous and subcutaneous pharmacokinetics of florfenicol in sheep.

Pharmacokinetic parameters of florfenicol were determined in 10 adult sheep (five wethers and five ewes) after a single 40 mg/kg intravenous (i.v.) dose, and three daily subcutaneous (s.c.) doses of 40 mg/kg of a commercial preparation (Nuflor((R))). The concentration of florfenicol in serum samples was assayed using a proprietary HPLC assay method, and pharmacokinetic parameters derived for individual animal data by each route using compartmental and noncompartmental approaches. Two animals (one male and one female) were excluded due to observed i.v. dosing problems, and a biexponential model was found to fit the i.v. data well for six of the other eight animals. Data from two males showed prolonged low concentrations of florfenicol in serum and were better fit by a three-compartment model. The mean +/- SD for the half-lives of the distribution and elimination phases for the six sheep best fit with a two-compartment model were 0.069 +/- 0.018 and 1.01 +/- 0.09 h respectively, and for the V(d(ss)) and clearances were 0.503 +/- 0.035 L/kg and 366 +/- 53 mL/h/kg respectively. The data collected during the s.c. multiple dose study were analyzed using noncompartmental methods only. The bioavailability (F%) after s.c. dosing was calculated in three ways to compare estimation methods as steady-state had not been reached and single dose s.c. data were not obtained past 24 h. Using the AUC(0--24) and AUC(0--> infinity ) from the first dose, the F% values averaged 27 and 40% respectively. Using the AUC(0--> infinity ) for all doses, the F% was 65%. Calculations of the mean time during which the serum concentration exceeded 0.5 and 1.0 microg/mL were 105 +/- 3.9 and 74.7 +/- 12.2 h respectively.

Serum pharmacokinetics and tissue and milk residues of oxytetracycline in goats following a single intramuscular injection of a long-acting preparation and milk residues following a single subcutaneous injection.

Separate groups of goats were used to determine drug depletion patterns in serum (n=10), tissue (n=20) and milk (n=8) following a single intramuscular (i.m.) dose of 20 mg/kg of a long-acting oxytetracycline (OTC) formulation (Liquamycin LA-200). Milk residues were also determined following a subcutaneous (s.c.) administration of the same product at the same dose. Serum samples were taken for 24 h post-treatment and tissues (fat, liver, kidney, muscle and injection site) collected at 4, 7, 14, 21 and 28 days following injection. Milk from lactating goats was collected every 12 h for 8 days following both the i.m. and s.c. treatments utilizing an intervening 5-week washout period. Residues in serum and tissue were measured using a microbial inhibition assay, while milk residues were measured using both a microbial inhibition assay and a validated HPLC method. The serum pharmacokinetic parameters of OTC in goats were determined, with a mean AUC=67.4 microg h/mL, mean terminal half-life=14.4 h, and apparent clearance=0.33 L/kg h. Tissue half-lives could not be determined with confidence because the collection times provided only two points at which residues could be measured for most tissues. Oxytetracycline residues in all goat tissue samples measured less then cattle tissue tolerance by 96 h postdosing. One-compartment model describing milk depletion data for i.m. and s.c. dosing had terminal slope half-lives of 20.1 and 36.1 h, respectively. By 96 h post-treatment none of the milk samples contained OTC residues in excess of the cattle milk tolerance (0.3 p.p.m.). For both milk and tissue, the upper-bound 99% confidence intervals for the samples taken from goats 96 h postdosing were lower than approved cow milk and tissue tolerances.

Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparation.

The pharmacokinetics of a long-acting oxytetracycline (OTC) formulation (Liquamycin LA-200) injected intramuscularly (i.m.) at a dose of 20 mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168+/-14.6 (microg ? h/mL) and was significantly less than the AUC for sheep (209+/-43 microg ? h/mL). Using the standard two-stage approach and a one-compartment model, the mean Cmax for the calves was 5.2+/-0.8 microg /mL, and for the sheep was 6.1+/-1.3 microg /mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08 L/kg for the calves and sheep respectively. Analysis of the data using the standard two-stage approach, the naive pooled-data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20 mg/kg OTC. Half-lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9 h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6 p.p.m.), muscle (2 p.p.m.) and kidney (12 p.p.m.) by 48 h, and in injection site muscle by 14 days after the single i.m. injection of 20 mg/kg.

Pharmacokinetics of ceftiofur sodium in exotic and domestic avian species.

The pharmacokinetics of ceftiofur sodium were determined in domestic chicks, turkey poults, adult cockatiels (Nymphicus hollandicus), and adult orange-winged Amazon parrots (Amazona amazonica) after subcutaneous (chicks and turkey poults and intramuscular (i.m.) dosing (cockatiels and Amazon parrots). Turkey poult data were best fit to a single exponential model with disappearance half-lives (t1/2) of 8.6, 7.4 and 5.6 h after doses of 0.12, 0.24 and 0.48 mg ceftiofur free acid equivalents (CFAE)/poult, respectively. Data from chicks were best fit to a biexponential model with primary and secondary half-lives of 2.2 and 7.5, 3.7 and 6.8, and 3.8 and 5.3 h after doses of 0.04, 0.08 and 0.16 mg CFAE/chick, respectively. Cockatiel and Amazon parrot data were best fit to a biexponential model with primary and secondary half-lives of 0.28 and 2.5, and 0.93 and 7.9 h, respectively, after doses of 10 mg CFAE/kg body weight. The maximum concentration (Cmax) and area under the concentration time curve (AUC) in chicks and poults were dose-proportional. The Cmax for cockatiels was 5.2 micrograms/mL and for Amazon parrots was 11 micrograms/mL. Clearance in cockatiels and Amazon parrots were 11.3 and 3.8 mL/min/kg, respectively, and reflected the much greater AUC seen in Amazon parrots. Clearance values of ceftiofur were similar in chicks and Amazon parrots, slightly greater in turkey poults and greatest in cockatiels. These results indicate that pharmacokinetic differences must be considered when establishing dosage regimens for different avian species.

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats.

Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.