Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration–time curve (AUC_0−∞), elimination half-life (t_1/2ʎz), total clearance (Cl_T) and volume of distribution at steady state (V_dss) were 6.64 ± 0.81 hr^*µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h^-1 kg^-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t_1/2ʎz, increased dose-normalized AUC_0-∞, and decreased Cl_T. In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.     

The pharmacokinetics of nitazoxanide active metabolite (tizoxanide) in goats and its protein binding ability in vitro

Zhao, Z., Xue, F., Zhang, L., Zhang, K., Fei, C., Zheng, W., Wang, X., Wang, M., Zhao, Z., Meng, X. The pharmacokinetics of nitazoxanide active metabolite (tizoxanide) in goats and its protein binding ability in vitro. J. vet. Pharmacol. Therap. 33 , 147–153. The pharmacokinetics of tizoxanide (T), the active metabolite of nitazoxanide (NTZ), and its protein binding ability in goat plasma and in the solutions of albumin and α‐1‐acid‐glycoprotein were investigated. The plasma and protein binding samples were analyzed using a high‐performance liquid chromatography (HPLC) assay with UV detection at 360 nm. The plasma concentration of T was detectable in goats up to 24 h. Plasma concentrations vs. time data of T after 200 mg/kg oral administration of NTZ in goats were adequately described by one‐compartment open model with first order absorption. As to free T, the values of t_1/2Ka, t_1/2Ke, T_max, C_max, AUC, V/F_(c), and Cl_(s) were 2.51 ± 0.41 h, 3.47 ± 0.32 h, 4.90 ± 0.13 h, 2.56 ± 0.25 μg/mL, 27.40 ± 1.54 (μg/mL) × h, 30.17 ± 2.17 L/kg, and 7.34 ± 1.21 L/(kg × h), respectively. After β‐glucuronidase hydrolysis to obtain total T, t_1/2ke, C_max, T_max, AUC increased, while the V/F_(c) and Cl_(s) decreased. Study of the protein binding ability showed that T with 4 μg/mL concentration in goat plasma and in the albumin solution achieved a protein binding percentage of more than 95%, while in the solution of α‐1‐acid‐glycoprotein, the percentage was only about 49%. This result suggested that T might have much more potent binding ability with albumin than with α‐1‐acid‐glycoprotein, resulting from its acidic property.     

Short‐term intake of β‐carotene‐supplemented diets enhances ovarian function and progesterone synthesis in goats

The effect of β‐carotene supplementation upon luteal activity, measured as number (CLT) and volume (VLT) of corpus luteum, and P4 synthesis in goats, was evaluated. Goats (n = 22, 34 months) were randomly assigned to one of two experimental groups: (i) β‐carotene [Beta, n = 10; body weight (BW = 44.8 ± 1.45 kg), body condition score (BCS = 3.25 ± 0.07)], and (ii) Control (Control, n = 12; BW = 45.30 ± 1.32 kg, BCS = 3.33 ± 0.06). Upon oestrus synchronization, the Beta group received 50 mg of β‐carotene per day during 35 days pre‐ and 17 days post‐ovulation. The day 4, 8, 12 and 16 post‐ovulation, blood samples were collected for quantification of serum P4 concentrations by radioimmmunoassay, and transrectal ultrasonographic scanning was performed at day 18 for evaluating CLT and VLT. Overall, CLT and VLT mean were 3.10 and 2211.1 mm³ respectively. The Beta‐goats depicted both the largest values for CLT (p = 0.07) and serum P4 levels (p = 0.05), with no differences (p = 0.53) for VLT between treatments. Results suggest a higher efficiency within the cellular‐enzymatic groups defining the steroidogenic pathways in the β‐carotene‐supplemented goats, generating a larger P4 synthesis. The last is essential for ovulation of healthy oocytes, maintenance of uterine quiescence, nourishment and survival of the embryo around implantation; all of them of paramount significance during the maternal recognition of pregnancy process.     

Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs

Brown, S.A., Jacobson, J.D., Hartsfield, S.M. Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs. J. vet. Pharmacol. Therap. 16 , 419–425. Midazolam, a water-soluble benzodiazepine tranquilizer, has been considered by some veterinary anaesthesiologists to be suitable as a combination anaesthetic agent when administered concurrently with ketamine because of its water solubility and miscibility with ketamine. However, the pharmacokinetics of midazolam have not been extensively described in the dog. Twelve clinically healthy mixed breed dogs (22.2–33.4 kg) were divided into two groups at random and were administered ketamine (10 mg/kg) and midazolam (0.5 mg/kg) either as an intravenous bolus over 30 s (group 1) or as an i.v. infusion in 0.9% NaCl (2 ml/kg) over 15 min. Blood samples were obtained immediately before the drugs were injected and periodically for 6 h afterwards. Serum concentrations were determined using gas chromatography with electron-capture detection. Serum concentrations were best described using a two-compartment open model and indicated a t_½α of 1.8 min and t_½β.p of 27.8 min after i.v. bolus, and t_½α f 1–35 min and t_½β of 31.6 min after i.v. infusion. The calculated pharmacokinetic coefficient B was significantly smaller after i.v. infusion (429 ± 244 ng/ml) than after i.v. bolus (888 ± 130 ng/ml, P = 0.004). Furthermore, AUC was significantly smaller after i.v. infusion (29 800 ±6120 ng/h/ml) than after i.v. bolus (42 500 ± 8460 ng/h/ml, P < 0.05), resulting in a larger Cl_B after i.v. infusion (17.4 ± 4.00 ml/min/kg than after i.v. bolus (12.1 ± 2.24 ml/min/kg, P < 0.05). No other pharmacokinetic value was significantly affected by rate of intravenous administration.     

Pharmacokinetics and selected behavioral responses to butorphanol and its metabolites in goats following intravenous and intramuscular administration

Objective To evaluate disposition of a single dose of butorphanol in goats after intravenous (IV) and intramuscular (IM) administration and to relate behavioral changes after butorphanol administration with plasma concentrations. Design Randomized experimental study. Animals Six healthy 3‐year‐old neutered goats (one male and five female) weighing 46.5 ± 10.5 kg (mean ± D). Methods Goats were given IV and IM butorphanol (0.1 mg kg^?1) using a randomized cross‐over design with a 1‐week interval between treatments. Heparinized blood samples were collected at fixed intervals for subsequent determination of plasma butorphanol concentrations using an enzyme linked immunosorbent assay (ELISA). Pharmacokinetic values (volume of distribution at steady state [Vd_SS], systemic clearance [Cl_TB], extrapolated peak plasma concentration [C₀] or estimated peak plasma concentration [C_MAX], time to estimated peak plasma concentration [T_MAX], distribution and elimination half‐lives [t_1/2], and bioavailability) were calculated. Behavior was subjectively scored. A two‐tailed paired t‐test was used to compare the elimination half‐lives after IV and IM administration. Behavioral scores are reported as median (range). A Friedman Rank Sums test adjusted for ties was used to analyze the behavioral scores. A logit model was used to determine the effect of time and concentration on behavior. A value of p < 0.05 was considered significant. Results Volume of distribution at steady state after IV administration of butorphanol was 1.27 ± 0.73 L kg^?1, and Cl_TB was 0.0096 ± 0.0024 L kg^?1 minute^?1. Extrapolated C₀ of butorphanol after IV administration was 146.5 ± 49.8 ng mL^?1. Estimated C_MAX after IM administration of butorphanol was 54.98 ± 14.60 ng mL^?1, and T_MAX was 16.2 ± 5.2 minutes; bioavailability was 82 ± 41%. Elimination half‐life of butorphanol was 1.87 ± 1.49 and 2.75 ± 1.93 hours for IV and IM administration, respectively. Goats became hyperactive after butorphanol administration within the first 5 minutes after administration. Behavioral scores for goats were significantly different from baseline at 15 minutes after IV administration and at 15 and 30 minutes after IM administration. Both time and plasma butorphanol concentration were predictors of behavior. Behavioral scores of all goats had returned to baseline by 120 minutes after IV administration and by 240 minutes after IM administration. Conclusions and Clinical Relevance The dose of butorphanol (0.1 mg kg^?1, IV or IM) being used clinically to treat postoperative pain in goats has an elimination half‐life of 1.87 and 2.75 hours, respectively. Nonpainful goats become transiently excited after IV and IM administration of butorphanol. Clinical trials to validate the efficacy of butorphanol as an analgesic in goats are needed.     

Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids

Ingvast‐Larsson, C., Högberg, M., Mengistu, U., Olsén, L., Bondesson, U., Olsson, K. Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids. J. vet. Pharmacol. Therap. 34 , 64–69. The pharmacokinetics and analgesic effect of the nonsteroidal anti‐inflammatory drug meloxicam (0.5 mg/kg) in goats were investigated. In a randomized, cross‐over design the pharmacokinetic parameters were investigated in adult goats (n = 8) after single intravenous and oral administration. The analgesic effect was evaluated in kids using a randomized, placebo controlled and blinded protocol. Kids received meloxicam (n = 6) once daily and their siblings (n = 5) got isotonic NaCl intramuscularly while still anaesthetized after cautery disbudding and injections were repeated on three consecutive days. In the adult goats after intravenous administration the terminal half‐life was 10.9 ± 1.7 h, steady‐state volume of distribution was 0.245 ± 0.06 L/kg, and total body clearance was 17.9 ± 4.3 mL/h/kg. After oral administration bioavailability was 79 ± 19%, C_max was 736 ± 184 ng/mL, T_max was 15 ±5 h, although the terminal half‐life was similar to the intravenous value, 11.8 ± 1.7 h. Signs of pain using a visual analogue scale were smaller in kids treated with meloxicam compared with kids treated with placebo on the first day after disbudding, but subsequently no difference in pain was noticeable. Plasma cortisol and glucose concentrations did not differ between the two groups.     

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady‐state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross‐over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one‐way anova ; P ≤ 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C_max was 14.4 ± 2.3 mcg/mL and elimination half‐life was 17.2 ± 3.6 h. After IV dosing, volume of distribution was 1.1 ± 0.25 L/kg, clearance was 58 ± 11 mL/h/kg and elimination t_1/2 was 12.9 ± 3.6 h. Oral bioavailability was 68 ± 12%; fraction of unbound drug approximated 60%. At steady‐state (4 days), differences occurred for for all parameters except C_max and C_min. Plasma C_max at steady‐state was 56 ± 12 mcg/mL, with 10% fluctuation between C_max and C_min. Plasma t_1/2 (h) was 23.52 ± 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 μg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.     

Bayesian population pharmacokinetic modeling of florfenicol in pigs after intravenous and intramuscular administration

Bayesian population pharmacokinetic models of florfenicol in healthy pigs were developed based on retrospective data in pigs either via intravenous (i.v.) or intramuscular (i.m.) administration. Following i.v. administration, the disposition of florfenicol was best described by a two‐compartment open model with the typical values of half‐life at α phase (t _1/2α), half‐life at β phase (t _1/2β), total body clearance (Cl), and volume of distribution (V _d) were 0.132 ± 0.0289, 2.78 ± 0.166 hr, 0.215 ± 0.0102, and 0.841 ± 0.0289 L kg^?1, respectively. The disposition of florfenicol after i.m. administration was best described by a one‐compartment open model. The typical values of maximum concentration of drug in serum (C _max), elimination half‐life (t _1/2Kel), Cl, and Volume (V ) were 5.52 ± 0.605 μg/ml, 9.96 ± 1.12 hr, 0.228 ± 0.0154 L hr^?1 kg^?1, and 3.28 ± 0.402 L/kg, respectively. The between‐subject variabilities of all the parameters after i.m. administration were between 25.1%–92.1%. Florfenicol was well absorbed (94.1%) after i.m. administration. According to Monte Carlo simulation, 8.5 and 6 mg/kg were adequate to exert 90% bactericidal effect against Actinobacillus pleuropneumoniae after i.v. and i.m. administration.     

The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs

The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high‐performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio‐respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Cl_area, Vd_area and T_1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Cl_area/F, Vd_area/F and T_1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.     

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus)

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross‐over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2‐week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half‐life (t_1/2β), the mean residence time (MRT), volume of distribution at steady‐state (V_d(ss)), volume of distribution based on terminal phase (V_d(z)), and the total body clearance (Cl_B) were (13.23 ± 2.24 and 1.95 ± 0.19 h), (10.06 ± 0.33 and 2.17 ± 0.20 h), (0.60 ± 0.08, and 2.35 ± 0.14 L/kg), (0.79 ± 0.12 and 2.49 ± 0.14 L/kg) and (0.69 ± 0.03 and 16.12 ± 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C_max (35.47 ± 2.52 and 37.50 ± 3.39 μg/mL), t_max (2.47 ± 0.31 and 2.47 ± 0.36 h), t_½β (11.79 ± 0.79 and 10.96 ± 0.56 h), V_d(z)/F (0.77 ± 0.06 and 0.89 ± 0.07 L/kg), Cl_B/F (0.76 ± 0.04 and 0.89 ± 0.07) and MRT (12.39 ± 0.40 and 12.08 ± 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C_max (0.71 ± 0.06 and 0.78 ± 0.10 μg/mL), t_max (2.07 ± 0.28 and 3.27 ± 0.28 h), t_½β (3.30 ± 0.25 and 3.83 ± 0.33 h), V_d(z)/F (6.2 ± 0.56 and 6.27 ± 0.77 L/kg), Cl_B/F (21.9 ± 1.46 and 18.83 ± 1.72) and MRT (3.68 ± 0.19 and 4.34 ± 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.     

The pharmacokinetics of cefadroxil over a range of oral doses and animal ages in the foal

To evaluate the effect of foal age on the pharmacokinetics of cefadroxil, five foals were administered cefadroxil in a single intravenous dose (5 mg/kg) and a single oral dose (10 or 20 mg/kg) at ages of 0.5, 1, 2, 3 and 5 months. Pharmacokinetic parameters of terminal elimination rate constant (β_po), oral mean residence time (MRT_po), mean absorption time (MAT), rate constant for oral absorption (K_a), bioavailability F, peak serum concentrations(C_max) and time of peak concentration (t_max), were evaluated in a repeated measures analysis over dose. Across animal ages, parameters for the intravenous dose did not change significantly over animal age (P 0.05). Mean values ± SEM were: β_IV = 0.633 ± 0.038 h^?1; Cl = 0.316 ± 0.010 L/kg/h; V_c = 0.196 ± 0.008 L/kg; V_area = 0.526 ± 0.024 L/kg; V_SS =0.374 ± 0.014 L/kg; MRT_iv = 1.22 ± 0.07 h; K_el = 1.67 ± 0.08 ^h?1. Following oral administration, drug absorption became faster with age (P < 0.05), as reflected by MRT_po, MAT, K_a and t_max. However, oral bioavailability (±SE) declined significantly (P < 0.05) from 99.6 ± 3.69% at 0.5 months to 14.5 ± 1.40% at 5 months of age. To evaluate a dose effect on the pharmacokinetic parameters, a series of oral doses (5, 10, 20 and 40 mg/kg) were administered to these foals at 1 month of age. β_po (0.548 ± 0.023 h^?1) and F (68.26 ± 2.43%) were not affected significantly by the size of the dose. C_max was approximately doubled with each two-fold increase in dose: 3.15 ± 0.15, 5.84 ± 0.48, 12.17 ± 0.93 and 19.71 ± 2.19 μg/mL. Dose-dependent kinetics were observed in MRT_po, MAT, K_a and t_max.     

Comparative Pharmacokinetics of Gentamicin after Intravenous,Intramuscular, Subcutaneous and Oral Administration in Broiler Chickens

The pharmacokinetics and bioavailability of gentamicin sulphate (5 mg/kg body weight) were studied in 50 female broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administration. Blood samples were collected at time 0 (pretreatment), and at 5, 15 and 30 min and 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Gentamicin concentrations were determined using a microbiological assay and Bacillus subtillis ATCC 6633 as a test organism. The limit of quantification was 0.2 μg/ml. The plasma concentration–time curves were analysed using non-compartmental methods based on statistical moment theory. Following i.v. administration, the elimination half-life (t _1/2β), the mean residence time (MRT), the volume of distribution at steady state (V _ss), the volume of distribution (V _d,area) and the total body clearance (Cl_B) were 2.93 ± 0.15 h, 2.08 ± 0.12 h, 0.77 ± 0.05 L/kg, 1.68 ± 0.39 L/kg and 5.06 ± 0.21 ml/min per kg, respectively. After i.m. and s.c. dosing, the mean peak plasma concentrations (C _max) were 11.37 ± 0.73 and 16.65 ± 1.36 μg/ml, achieved at a post-injection times (t _max) of 0.55 ± 0.05 and 0.75 ± 0.08 h, respectively. The t _1/2β was 2.87 ± 0.44 and 3.48 ± 0.37 h, respectively after i.m. and s.c. administration. The V _d,area and Cl_B were 1.49 ± 0.21 L/kg and 6.18 ± 0.31 ml/min per kg, respectively, after i.m. administration and were 1.43 ± 0.19 L/kg and 4.7 ± 0.33 ml/min per kg, respectively, after s.c. administration. The absolute bioavailability (F) of gentamicin after i.m. administration was lower (79%) than that after s.c. administration (100%). Substantial differences in the resultant kinetics data were obtained between i.m. and s.c. administration. The in vitro protein binding of gentamicin in chicken plasma was 6.46%.     

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T_1/2) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T_1/2 = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg⁻¹ min⁻¹) compared to maropitant (T_1/2 = 52.73 min ± 13.823 ml kg⁻¹ min⁻¹, CL = 178.57 ± 70.55) or morphine alone at higher doses (T_1/2 = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg⁻¹ min⁻¹). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.     

Florfenicol pharmacokinetics in healthy adult alpacas after subcutaneous and intramuscular injection

Holmes, K., Bedenice, D., Papich, M. G. Florfenicol pharmacokinetics in healthy adult alpacas after subcutaneous and intramuscular injection. J. vet. Pharmacol. Therap.  35 , 382–388. A single dose of florfenicol (Nuflor^®) was administered to eight healthy adult alpacas at 20 mg/kg intramuscular (i.m.) and 40 mg/kg subcutaneous (s.c.) using a randomized, cross‐over design, and 28‐day washout period. Subsequently, 40 mg/kg florfenicol was injected s.c. every other day for 10 doses to evaluate long‐term effects. Maximum plasma florfenicol concentrations (C_max, measured via high‐performance liquid chromatography) were achieved rapidly, leading to a higher C_max of 4.31 ± 3.03 μg/mL following administration of 20 mg/kg i.m. than 40 mg/kg s.c. (C_max: 1.95 ± 0.94 μg/mL). Multiple s.c. dosing at 48 h intervals achieved a C_max of 4.48 ± 1.28 μg/mL at steady state. The area under the curve and terminal elimination half‐lives were 51.83 ± 11.72 μg/mL·h and 17.59 ± 11.69 h after single 20 mg/kg i.m. dose, as well as 99.78 ± 23.58 μg/mL·h and 99.67 ± 59.89 h following 40 mg/kg injection of florfenicol s.c., respectively. Florfenicol decreased the following hematological parameters after repeated administration between weeks 0 and 3: total protein (6.38 vs. 5.61 g/dL, P < 0.0001), globulin (2.76 vs. 2.16 g/dL, P < 0.0003), albumin (3.61 vs. 3.48 g/dL, P = 0.0038), white blood cell count (11.89 vs. 9.66 × 10³/μL, P < 0.044), and hematocrit (27.25 vs. 24.88%, P < 0.0349). Significant clinical illness was observed in one alpaca. The lowest effective dose of florfenicol should thus be used in alpacas and limited to treatment of highly susceptible pathogens.     

The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid

Ceftiofur sodium is a third-generation cephalosporin antibiotic. It is possible that non-steroidal anti-inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle. Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin. In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter. The organic anion transporter substrate used in this evaluation was probenecid. Ten healthy, non-pregnant, non-lactating dairy cows were used in a randomized complete three-way crossover design. In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus. For treatment with ceftiofur sodium alone, the mean volume of distribution at steady-state V_d(33) was 0.2 ± 0.06 L/kg, the mean volume of distribution by the area method V_d(area) was 0.38 ± 0.22 L/kg, mean residence time (MRT) was 6.5 ± 1.8 h, mean residence time in peripheral tissues (MRT_p) was 2.6 ± 1.0 h, total body clearance (Cf) was 0.032 ± 0.013 L/kg/h and elimination rate constant (P) was 0.097 ± 0.044 h^-1(mean ± standard deviation). No statistically significant changes were detected as a result of preceding treatment with aspirin. Preceding treatment with probenecid resulted in a decrease in both Cl (0.007 ± 0.005 L/kg/h) and MRT_p (0.89 ± 0.45 h). These results suggest that ceftiofur or its metabolites may interact with the organic anion transporter, but that consideration of alterations to dose and dose interval may not be necessary when ceftiofur sodium is administered to the cow concomitantly with a single dose of aspirin.     

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 and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos)

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross‐over design with a washout period between doses. Mean (±SD) C_max following IM injection was 1.6 (±0.8) µg/ml with T_max at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (V_D) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min^?1 kg^?1. Elimination half‐lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.     

Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan® in rats

Alfaxalone (3α‐hydroxy‐5α‐pregnane‐11, 20‐dione) is a neuroactive steroid with anaesthetic properties and a wide margin of safety. The pharmacokinetic properties of alfaxalone administered intravenously and intraperitoneally in rats (n = 28) were investigated. Mean t_1/2elim for 2 and 5 mg/kg i.v. was 16.2 and 17.6 min, respectively, but could not be estimated for IP dosing, due to sustained plasma levels for up to 60 min after injection. Cl_p for i.v. injection was calculated at 57.8 ± 23.6 and 54.3 ± 6.8 mL/min/kg, which were 24.5% and 23% of cardiac output, respectively. The observed C_max was 3.0 mg/L for IP administration, and 2.2 ± 0.9 and 5.2 ± 1.3 mg/L for 2 and 5 mg/kg i.v. administration, respectively. AUC_0–60 was 96.2 min·mg/L for IP dosing. The relative bioavailability for IP dosing was 26% and 28% compared to i.v. dosing. Differences in t_1/2elim and Cl_p from previous pharmacokinetic studies in rats are likely due to variations in alfaxalone formulation rather than sex differences. Alfaxan^® given IP caused sustained levels of alfaxalone, no apnoea and longer sleep times than i.v. dosing, although immobilization was not induced in 30% of rats given Alfaxan^® IP. A pharmacodynamic study of the effects of combining IP injection of Alfaxan^® with other premedication agents is worthwhile, to determine whether improved anaesthesia induction could ultimately provide an alternative anaesthetic regimen for rats.     

DIURETIC RENAL SCINTIGRAPHY IN NORMAL CATS

The purpose of this study was to develop a protocol for diuretic renal scintigraphy (renography) in cats and describe normal findings. ^99mTc‐DTPA renal scintigraphy was performed twice in 10 healthy cats. Furosemide or saline were injected 4.5 min after radiopharmaceutical administration for the diuretic or control scan, respectively. A dynamic acquisition was performed for 8 min. The following parameters were evaluated: (1) global and individual glomerular filtration rate (GFR); (2) shape of the time–activity curve (TAC); (3) time of peak (TOP); (4) individual kidney excretion half‐time (T_1/2) of the radiopharmaceutical; (5) percentage of maximum activity measured at the end of the study. Global GFR in the control studies (2.79±0.83 ml/min/kg, mean±SD) did not differ significantly from the diuretic scans (2.34±0.51 ml/min/kg). The shape of most (16/20) TAC of diuretic renograms was similar to those of control renograms. The TOP of the diuretic renogram curves was 3.06±0.58 min, and did not differ from that of the control scans (3.01±0.61 min). T_1/2 of the diuretic renograms was significantly shorter (5.15±0.83 min) than that of the control renograms (6.31±1.50 min). A significantly lower percentage of maximum activity was present at the end of the study in diuretic renograms (median: 47.25%; range: 33.60–59.60%) compared with control renograms (63.40%; 30.00–69.40%). Diuretic renal scintigraphy is a noninvasive and fast procedure to perform in cats. The applicability of this technique needs to be investigated in patients with significantly impaired renal function and obstructive uropathies.