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

Clothier, K. A., Leavens, T., Griffith, R. W., Wetzlich, S. E., Baynes, R. E., Riviere, J. E., Tell, L. A. Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J. vet. Pharmacol. Therap.  35 , 113–120. 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 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 t_1/2λz (67.20 h; harmonic). Mean milk pharmacokinetic parameters (±SD) following 45 days of sampling were as follows: C_max (1594 ± 379.23 ng/mL); T_max (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.     

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

Dechant, J. E., Rowe, J. D., Byrne, B. A., Wetzlich, S. E., Kieu, H. T., Tell, L. A. Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos). J. vet. Pharmacol. Therap.  36 , 122–129. 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 C_max (2.7 ± 0.9 μg/mL); T_max (36 ± 0 h); area under the curve AUC_0→∞ (199.2 ± 42.1 μg·h/mL); terminal phase rate constant λz (0.02 ± 0.003/h); and terminal phase rate constant half‐life t_1/2λz (44.7 h; harmonic). Mean terminal pharmacokinetic parameters (±SD) following three administrations of CCFA were C_max (2.0 ± 0.4 μg/mL); T_max (17.3 ± 16.3 h); AUC_0→∞ (216.8 ± 84.5 μg·h/mL); λz (0.01 ± 0.003/h); and t_1/2λz (65.9 h; harmonic). The terminal phase rate constant and the T_max were significantly different between single and multiple administrations. Local reactions were noted in two alpacas following multiple CCFA administrations.     

Pharmacokinetics of carfentanil and naltrexone in domestic goats (Capra hircus).

Using a crossover study design, the pharmacokinetics of carfentanil and naltrexone after i.v., i.m., and s.c. administration were determined in eight domestic goats (Capra hircus). Serial blood samples were taken up to 120 hr after carfentanil administration, and the plasma drug concentrations were determined using liquid chromatography and mass spectroscopy. All goats were immobilized with 40 microg/kg carfentanil i.m., although the resulting neurologic effects varied considerably. Plasma profiles showed rapid carfentanil absorption and a simple biphasic decline for 12-48 hr. Naltrexone given at 100 mg naltrexone/mg carfentanil 30 min after carfentanil administration produced rapid reversal of immobilization after all routes of administration. Variable fluctuations in the naltrexone plasma concentrations during the first 2.5-3.5 hr were observed, followed by a more consistent biphasic decline. The time to standing was significantly shorter after i.v. compared with s.c. naltrexone, although the time difference (1 min) had little clinical relevance. No statistically significant differences between the naltrexone pharmacokinetic parameters measured for the three routes of naltrexone administration were identified, although the recoveries after i.m. administration were, subjectively, the smoothest. The carfentanil half-life did not differ significantly in the goats given naltrexone by different routes. Although it is currently recommended that the naltrexone dose be divided into s.c. and i.v. portions, this practice does not appear to offer any benefit.     

Pharmacokinetics of erythromycin in nonlactating and lactating goats after intravenous and intramuscular administration

The objectives of this work were to compare the pharmacokinetics of erythromycin administered by the intramuscular (i.m.) and intravenous (i.v.) routes between nonlactating and lactating goats and to determine the passage of the drug from blood into milk. Six nonpregnant, nonlactating and six lactating goats received erythromycin by the i.m. (15 mg/kg) and the i.v. (10 mg/kg) routes of administration. Milk and blood samples were collected at predetermined times. Erythromycin concentrations were determined by microbiological assay. Results are reported as mean +/- SD. Comparison of the pharmacokinetic profiles between nonlactating and lactating animals after i.v. administration indicated that significant differences were found in the mean body clearance (8.38 +/- 1.45 vs. 3.77 +/- 0.83 mL/kg x h respectively), mean residence time (0.96 +/- 0.20 vs. 3.18 +/- 1.32 h respectively), area under curve from 0 to 12 h (AUC(0-12)) (1.22 +/- 0.22 vs. 2.76 +/- 0.58 microg x h/mL respectively) and elimination half-life (1.41 +/- 1.20 vs. 3.32 +/- 1.34 h); however, only AUC(0-12) showed significant differences after the i.m. administration. Passage of erythromycin in milk was high (peak milk concentration/peak serum concentration, 2.06 +/- 0.36 and AUC(0-12milk)/AUC(0-12serum),6.9 +/- 1.05 and 2.37 +/- 0.61 after i.v. and i.m. administrations respectively). We, therefore, conclude that lactation affects erythromycin pharmacokinetics in goats.     

Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline‐free acid following subcutaneous administration in domestic goats

Pharmacokinetic (PK)–pharmacodynamic (PD) integration of crystalline ceftiofur‐free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high‐performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half‐life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time–kill curves for P. multocida demonstrated a time‐dependent killing action of drug. Considering target serum concentration of 0.20 μg/mL, PK‐PD values for AUC_24 h/MIC₉₀ and T > MIC₉₀, respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10–14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single‐dose administration. Based on MPC = 1.40 μg/mL for P. multocida, the PK‐PD indices, viz. T > MPC and AUC₂₄/MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida.     

Seroprevalence of Mycobacterium avium subspecies paratuberculosis in Korean black goats (Capra hircus aegagrus)

In total, 582 sera from 116 black goat herds were analyzed by a commercially available ELISA kit to monitor the seroprevalence of Mycobacterium avium subspecies paratuberculosis (Mpt) in Korean black goats (Capra hircus aegagrus). The mean number of goats sampled per herd was 5.11, 4.66, and 5.38 for the northern, central, and southern regions of Korea, respectively. The apparent regional prevalence of Mpt was estimated at 18.2-38.2% and 4.6-15.3% for herds and goats, respectively. The Mpt-positive goats were predominantly detected in the south (n=28), compared to either the northern (n=9) or central (n=11) regions (chi=14.459, P<0.05). Our findings indicate that Mpt is prevalent among the goat population, but regional variation exists.     

Pharmacokinetics of levosulpiride after single‐dose administration in goats (Capra hircus) by different routes of administration

Levosulpiride (LSP) is the l‐enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross‐over design (3 × 3 Latin‐square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5–4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.     

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.     

The absence of detectable fetal microchimerism in nontransgenic goats (Capra aegagrus hircus) bearing transgenic offspring

Regulations for the disposal of genetically engineered animals are strict due to concern for their inappropriate introduction into the food chain, and of the possible public health and environmental impacts of these organisms. Nontransgenic animals that give birth to transgenic offspring are treated as if they are transgenic due to concern of fetal cells crossing the placental barrier and residing in the mother (fetal-maternal microchimerism). Determining whether or not fetal-fetal or fetal-maternal transfer of DNA or cells occurs during caprine gestation is critical to effectively protect the public without culling animals that pose no risk. Additionally, fetal-maternal transfer, should it exist in the goat, could contraindicate the rebreeding of nontransgenic dams due to the possible transfer of fetal cells from 1 pregnancy to the fetus of subsequent pregnancies. Fetal-maternal transfer in Capra hircus has not been reported in the literature, although it has been reported in another ruminant, Bos taurus. We examined blood from nontransgenic dams that carried transgenic offspring using a PCR method sensitive enough to detect the presence of a spider silk transgene to a 1:100,000 dilution. At this sensitivity, we did not detect the occurrence of fetal-maternal transfer in 5 nontransgenic dams. Likewise, fetal-fetal transfer was not observed from a transgenic to a nontransgenic twin in utero. To test tissue-specific expression of the silk transgene, proteins purified from standard necropsy tissue from a lactating transgenic dam were examined by Western blot analysis. Silk protein expression was only observed in mammary tissue consistent with the tissue specificity of the β-casein promoter used in the transgenic construct. We report evidence collected from a limited caprine breeding pool against transfer of transgenes in utero from fetus to dam and fetus to fetus. In addition, we show evidence that the β-casein promoter in our expression construct is not expressed ectopically as previously suggested. These results suggest that transgene transfer in utero does not occur, but further study is warranted with a larger sample group to confirm these results.     

Pharmacokinetics of a long-acting ceftiofur formulation (ceftiofur crystalline free acid) in the ball python (Python regius)

The objective of this study was to determine the pharmacokinetics of a long-acting formulation of ceftiofur crystalline-free acid (CCFA) following intramuscular injection in ball pythons (Python regius). Six adult ball pythons received an injection of CCFA (15 mg/kg) in the epaxial muscles. Blood samples were collected by cardiocentesis immediately prior to and at 0.5, 1, 2, 4, 8, 12, 18, 24, 48, 72, 96, 144, 192, 240, 288, 384, 480, 576, 720, and 864 hr after CCFA administration. Plasma ceftiofur concentrations were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was applied to the data. Maximum plasma concentration (Cmax) was 7.096 +/- 1.95 microg/ml and occurred at (Tmax) 2.17 +/- 0.98 hr. The area under the curve (0 to infinity) for ceftiofur was 74.59 +/- 13.05 microg x h/ml and the elimination half-life associated with the terminal slope of the concentration-time curve was 64.31 +/- 14.2 hr. Mean residence time (0 to infinity) was 46.85 +/- 13.53 hr. CCFA at 15 mg/kg was well tolerated in all the pythons. Minimum inhibitory concentration (MIC) data for bacterial isolates from snakes are not well established. For MIC values of < or =0.1 microg/ml, a single dose of CCFA (15 mg/kg) provides adequate plasma concentrations for at least 5 days in the ball python. For MICs > or =0.5 microg/ml, more frequent dosing or a higher dosage may be required.     

Pharmacokinetics and milk penetration of moxifloxacin after intravenous and subcutaneous administration to lactating goats

The pharmacokinetics of moxifloxacin was studied following intravenous (IV) and subcutaneous (SC) administration of 5 mg/kg to healthy lactating goats (n = 6). Moxifloxacin concentrations were determined by high performance liquid chromatography assay with fluorescence detection. The moxifloxacin plasma concentration versus time data after IV administration could best be described by a two compartment open model. The disposition of SC administered moxifloxacin was best described by a one-compartment model. The plasma moxifloxacin clearance (Cl) for the IV route was 0.43 +/- 0.02 L/kg (mean +/- SE). The steady-state volume of distribution (Vss) was 0.79 +/- 0.08 L/kg. The terminal half-life (t1/2lambdaz) was 1.94 +/- 0.41 and 2.98 +/- 0.48 h after IV and SC administration, respectively. The absolute bioavailability was 96.87 +/- 10.27% after SC administration. Moxifloxacin penetration from blood to milk was quick for both routes of administration and the high AUCmilk/AUCplasma and Cmax-milk/Cmax-plasma ratios reached indicated a wide penetration of moxifloxacin into the milk. From these data, it appears that a 5 mg/kg SC dose of moxifloxacin would be effective in lactating goats against bacterial isolates with MIC < or = 0.20 microg/mL in plasma and MIC < or = 0.40 microg/mL in milk.     

Pharmacokinetics of ceftiofur in plasma and uterine secretions and tissues after subcutaneous postpartum administration in lactating dairy cows

A study was conducted to measure concentrations of potentially active ceftiofur derivatives, in plasma, in uterine tissues (endometrium and caruncles) and in uterine secretions at different time points after a single subcutaneous administration of ceftiofur hydrochloride (Excenel RTU Sterile Suspension) at the dose of 1 mg/kg body weight in Holstein-Friesian dairy cows. The animals (n=4) were injected within 24 h of calving, after expulsion of the foetal membranes. Plasma, lochial fluid, caruncles and endometrium were collected before ceftiofur hydrochloride administration and at 1, 2, 4, 8, 12 and 24 h after treatment. For each cow the concentrations of ceftiofur in the biological matrices were quantified using an high-performance liquid chromatography (HPLC) assay. The limit of quantification of the method was 0.1 microg/mL for plasma and 0.1 microg/g for lochial fluid, caruncles and endometrium. The concentrations of potentially active ceftiofur derivatives detected in plasma reached a maximum of 2.85 +/- 1.11 microg/mL at 2 h and decreased to 0.64 +/- 0.14 microg/mL at 24 h after administration. In lochial fluid, these concentrations reached a maximum of 0.97 +/- 0.25 microg/g at 4 h and decreased to 0.22 +/- 0.21 microg/g at 24 h after administration. In endometrium, these concentrations reached a maximum of 2.23 +/- 0.82 microg/g at 4 h and decreased to 0.56 +/- 0.14 microg/g at 24 h following the injection, whereas these levels in caruncles were 0.96 +/- 0.45 and 0.60 +/- 0.39 microg/g obtained at 8 and 24 h, respectively. At the dose of 1 mg/kg body weight in healthy dairy cows, subcutaneous administration of ceftiofur (as ceftiofur hydrochloride) after parturition results in concentrations of ceftiofur derivatives in uterine tissues and in lochial fluid that exceed the reported minimal inhibitory concentrations (MICs) for the common pathogens (Escherichia coli, Fusobacterium necrophorum, Bacteroides spp., and Arcanobacterium pyogenes) associated with acute puerperal metritis.     

Distribution of ceftiofur into Mannheimia haemolytica‐infected tissue chambers and lung after subcutaneous administration of ceftiofur crystalline free acid sterile suspension

Washburn, K., Johnson, R., Clarke, C, Anderson, K. Distribution of ceftiofur into Mannheimia haemolytica‐infected tissue chambers and lung after subcutaneous administration of ceftiofur crystalline free acid sterile suspension. J. vet. Pharmacol. Therap. 33 , 141–146. The objective of this study was to evaluate the penetration of ceftiofur‐ and desfuroylceftiofur‐related metabolites (DCA) into sterile and infected tissue chambers, lung tissue and disposition of DCA in plasma across four different sacrifice days postdosing. Twelve healthy calves were utilized following implantation with tissue chambers in the paralumbar fossa. Tissue chambers in each calf were randomly inoculated with either Mannheimia haemolytica or sterile PBS. All calves were dosed with ceftiofur crystalline free acid sterile suspension (CCFA‐SS) subcutaneously in the ear pinna. Calves were randomly assigned to 4 groups of 3 to be sacrificed on days 3, 5, 7 and 9 postdosing. Prior to euthanasia, plasma and tissue chamber fluid were collected, and immediately following euthanasia, lung tissue samples were obtained from four different anatomical sites DCA concentration analysis. Results of our study found that, in general, DCA concentrations followed a rank order of plasma > infected tissue chamber fluid > noninfected tissue chamber fluid > lung tissue. Data also indicated DCA concentrations remained above the therapeutic threshold of 0.2 μg/mL for plasma and chamber fluid and 0.2 μg/g for lung tissue for at least 7 days post‐treatment.     

Pharmacokinetics of cefonicid in lactating goats after intravenous,intramuscular and subcutaneous administration,and after a long-acting formulation for subcutaneous administration

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (V_ss) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.     

Investigation of the primary cause of hypoadrenocorticism in South African angora goats (Capra aegagrus): a comparison with Boer goats (Capra hircus) and Merino sheep (Ovis aries)

Our objective was to identify the primary site of the reduced adrenal function in South African Angora goats (Capra aegagrus) that causes a decrease in cortisol production and leads to severe losses of Angora goats during cold spells. Angora goats, Boer goats (Capra hircus), and Merino sheep (Ovis aries) were assigned to three intravenous treatments: 1) insulin, 2) corticotropin-releasing factor (CRF), and 3) ACTH. Blood cortisol concentrations were determined over a 90-min period to determine any differences in the response of the experimental animals to these treatments. For both the insulin and ACTH treatments, cortisol concentrations were less in Angora goats than in the other experimental animals. The adrenal gland was subsequently investigated as a possible cause for the observed hypoadrenocorticism. Primary adrenal cell cultures were prepared from these species, subjected to different treatments, and the cortisol production determined. Upon pregnenolone (PREG) addition, all the experimental animals' cortisol production increased significantly, with the production in Boer goats higher (P<.01) when compared with that in the other species. The stimulation of cortisol biosynthesis by ACTH was only obtained for Boer goats and Merino sheep. The stimulation of cortisol production by forskolin and cholera toxin were compared with ACTH, and, for Angora goats, only cholera toxin caused a significant increase in cortisol production. For Boer goats, no difference (P>.05) between the PREG, ACTH, forskolin, or cholera toxin treatments were observed. The Merino adrenal cells were increasingly stimulated in the following order: PREG, ACTH, forskolin, and cholera toxin (forskolin and cholera toxin stimulated cortisol production to the same extent). This investigation of the hypothalamic-pituitary-adrenocortical axis, therefore, identified the adrenal gland as the primary site of the Angora's hypoadrenocorticism.     

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 AUC _0–∞ 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 AUC _0–∞ 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 C _max, and serum concentrations were dose-proportional after the multiple dosing regimen.