Pharmacokinetics of intravenous and transdermal fentanyl in alpacas

The purpose of the study was to determine pharmacokinetics of fentanyl after intravenous (i.v.) and transdermal (t.d.) administration to six adult alpacas. Fentanyl was administered i.v. (2 μg/kg) or t.d. (nominal dose: 2 μg kg^?1 hr^?1). Plasma concentrations were determined using liquid chromatography–mass spectrometry. Heart rate and respiratory rate were assessed. Extrapolated, zero‐time plasma fentanyl concentrations were 6.0 ng/ml (1.7–14.6 ng/ml) after i.v. administration, total plasma clearance was 1.10 L hr^?1 kg^?1 (0.75–1.40 L hr^?1 kg^?1), volumes of distribution were 0.30 L/kg (0.10–0.99 L/kg), 1.10 L/kg (0.70–2.96 L/kg) and 1.5 L/kg (0.8–3.5 L/kg) for V₁, V₂, and V_ss, respectively. Elimination half‐life was 1.2 hr (0.5–4.3 hr). Mean residence time (range) after i.v. dosing was 1.30 hr (0.65–4.00 hr). After t.d. fentanyl administration, maximum plasma fentanyl concentration was 1.20 ng/ml (0.72–3.00 ng/ml), which occurred at 25 hr (8–48 hr) after patch placement. The area under the plasma fentanyl concentration‐vs‐time curve (extrapolated to infinity) after t.d. fentanyl was 61 ng*hr/ml (49–93 ng*hr/ml). The dose‐normalized bioavailability of fentanyl from t.d. fentanyl in alpacas was 35.5% (27–64%). Fentanyl absorption from the t.d. fentanyl patch into the central compartment occurred at a rate of approximately 50 μg/hr (29–81 μg/hr) between 8 and 72 hr after patch placement.     

Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration

The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high‐performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady‐state volume of distribution (V_ss) were 0.15 (0.13–0.18) L hr^?1 kg^?1 and 1.23 (0.93–1.53) L/kg, respectively. The median (range) elimination half‐life (t_1/2) after i.v. and p.o. administration was 7.90 (7.62–8.18) and 12.79 (11.22–16.24) hr, respectively. Oral bioavailability varied from 0.43 to 0.99 (median: 0.66). Following oral administration, maximum plasma concentration (C_max; median: 0.72, range: 0.55–0.93 μg/ml) was achieved in 8 (range 6–12) hr. The in vitro plasma protein binding of posaconazole incubated at 37°C was 99.25 ± 0.29%. Consideration of posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets for some yeasts such as disseminated candidiasis suggests that posaconazole could be an efficacious treatment for cryptococcosis in koalas.     

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3–4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half‐life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr^?1 kg^?1, volume of distribution at steady‐state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half‐life, volume of distribution at steady‐state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg^?1 hr^?1. Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ , as lower limits can influence estimated parameters, such as elimination half‐life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.     

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.     

Pharmacokinetics of an intravenous and oral dose of enrofloxacin in white rhinoceros (Ceratotherium simum)

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic‐pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half‐life, area under the curve (AUC_tot), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 μg ml^?1 hr^?1, 0.19 ± 0.04 L h^?1 kg^?1, and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC₂₄: MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 μg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.     

Pharmacokinetics of norfloxacin after intravenous,intramuscular and subcutaneous administration to rabbits

The disposition kinetics of norfloxacin, after intravenous, intramuscular and subcutaneous administration was determined in rabbits at a single dose of 10 mg/kg. Six New Zealand white rabbits of both sexes were treated with aqueous solution of norfloxacin (2%). A cross‐over design was used in three phases (2 × 2 × 2), with two washout periods of 15 days. Plasma samples were collected up to 72 hr after treatment, snap‐frozen at ?45°C and analysed for norfloxacin concentrations using high‐performance liquid chromatography. The terminal half‐life for i.v., i.m. and s.c. routes was 3.18, 4.90 and 4.16 hr, respectively. Clearance value after i.v. dosing was 0.80 L/h·kg. After i.m. administration, the absolute bioavailability was (mean ± SD ) 108.25 ± 12.98% and the C_max was 3.68 mg/L. After s.c. administration, the absolute bioavailability was (mean ± SD ) 84.08 ± 10.36% and the C_max was 4.28 mg/L. As general adverse reactions were not observed in any rabbit and favourable pharmacokinetics were found, norfloxacin at 10 mg/kg after i.m. and s.c. dose could be effective in rabbits against micro‐organisms with MIC ≤0.14 or 0.11 μg/mL , respectively.     

Pharmacokinetics of cefquinome in red‐eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections

The purpose of this study was to evaluate the pharmacokinetics of cefquinome (CFQ ) following single intravenous (IV ) or intramuscular (IM ) injections of 2 mg/kg body weight in red‐eared slider turtles. Plasma concentrations of CFQ were determined by high‐performance liquid chromatography and analyzed using noncompartmental methods. The pharmacokinetic parameters following IV injection were as follows: elimination half‐life (t _1/2λz) 21.73 ± 4.95 hr, volume of distribution at steady‐state (V _dss) 0.37 ± 0.11 L/kg, area under the plasma concentration–time curve (AUC _0–∞) 163 ± 32 μg hr^?1 ml^?1, and total body clearance (Cl_T) 12.66 ± 2.51 ml hr^?1 kg^?1. The pharmacokinetic parameters after IM injection were as follows: peak plasma concentration (C _max) 3.94 ± 0.84 μg/ml, time to peak concentration (T _max) 3 hr, t _1/2λz 26.90 ± 4.33 hr, and AUC _0–∞ 145 ± 48 μg hr^?1 ml^?1. The bioavailability after IM injection was 88%. Data suggest that CFQ has a favorable pharmacokinetic profile with a long half‐life and a high bioavailability in red‐eared slider turtles. Further studies are needed to establish a multiple dosage regimen and evaluate clinical efficacy.     

Pharmacokinetics,disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical,oral, and intravenous administration

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v. ), oral (p.o. ), and topical (TOP ) administration of dimethyl sulfoxide (DMSO ). The plasma concentration–time curve following a 15‐min i.v. infusion of DMSO was described by a two‐compartment model. Median and range of alpha (t _1/2α) and beta (t _1/2β) half‐lives were 0.029 (0.026–0.093) and 14.1 (6.6–16.4) hr, respectively. Plasma concentration–time curves of DMSO following p.o. and TOP administration were best described by one‐compartment absorption and elimination models. Following the p.o. administration, median absorption (t _1/2ab) and elimination (t _1/2e) half‐lives were 0.15 (0.01–0.77) and 15.5 (8.5–25.2) hr, respectively. The plasma concentrations of DMSO were 47.4–129.9 μg/ml, occurring between 15 min and 4 hr. The fractional absorption (F ) during a 24‐hr period was 47.4 (22.7–98.1)%. Following TOP administrations, the median t _1/2ab and t _1/2e were 1.2 (0.49–2.3) and 4.5 (2.1–11.0) hr, respectively. Plasma concentrations were 1.2–8.2 μg/ml occurring at 2–4 hr. Fractional absorption following TOP administration was 0.48 (0.315–4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2–6.7) ml hr^?1 kg^?1. The corrected clearances (Cl_F ) for p.o. and TOP administrations were 2.9 (1.1–5.5) and 4.5 (0.52–18.2) ml hr^?1 kg^?1.     

Pharmacokinetics of marbofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration

To evaluate the fate and disposition of marbofloxacin (MBF) in freshwater crocodiles (Crocodylus siamensis), MBF was administered either intravenously (i.v.) or intramuscularly (i.m.) at a dosage of 2.0 mg/kg body weight. The concentrations of MBF in plasma were measured using high‐performance liquid chromatography equipped with a fluorescence detector. The concentrations of MBF in the plasma were measurable up to 144 h after i.v. and i.m. administration. After the first 45 min, the mean pharmacokinetic profiles produced by the two administration routes were almost identical. No statistically significant differences in the pharmacokinetic parameters between the groups were observed. The half‐life was long (about 2.5 days), the volume of distribution was large (about 1.44 L/kg), λz was small (0.01 h^?1), and the clearance was slow (22.6 mL/h/kg). The absolute i.m. bioavailability (F%) was 105.36%. The dose of MBF administered in this study seems to produce appropriate PK‐PD parameters that predict antibacterial success for disease caused by susceptible bacteria. More studies are warranted to evaluate the likely residues after administration of multiple doses.     

Pharmacokinetics of orbifloxacin in crucian carp (Carassius auratus) after intravenous and intramuscular administration

The pharmacokinetics of orbifloxacin was studied after a single dose (7.5 mg/kg) of intravenous or intramuscular administration to crucian carp (Carassius auratus ) reared in freshwater at 25°C. Plasma samples were collected from six fish per sampling point. Orbifloxacin concentrations were determined by high‐performance liquid chromatography with a 0.02 μg/ml limit of detection, then were subjected to noncompartmental analysis. After intravenous injection, initial concentration of 5.83 μg/ml, apparent elimination rate constant (λ_z) of 0.039 hr^?1, apparent elimination half‐life (T_1/2λz) of 17.90 hr, systemic total body clearance (Cl) of 75.47 ml hr^?1 kg^?1, volume of distribution (Vz) of 1,948.76 ml/kg, and volume of distribution at steady‐state (Vss) of 1,863.97 ml/kg were determined, respectively. While after intramuscular administration, the λ_z, T _1/2λz, mean absorption time (MAT ), absorption half‐life (T _1/2ka), and bioavailability were determined as 0.027 hr^?1, 25.69, 10.26, 7.11 hr, and 96.46%, respectively, while the peak concentration was observed as 3.11 ± 0.06 μg/ml at 2.0 hr. It was shown that orbifloxacin was completely but relatively slowly absorbed, extensively distributed, and slowly eliminated in crucian carp, and an orbifloxacin dosage of 10 mg/kg administered intravenously or intramuscularly would be expected to successfully treat crucian carp infected by strains with MIC values ≤0.5 μg/ml.     

Disposition of levetiracetam in healthy adult horses

Nine horses received 20 mg/kg of intravenous (LEV_IV ); 30 mg/kg of intragastric, crushed immediate release (LEV_CIR ); and 30 mg/kg of intragastric, crushed extended release (LEV_CER ) levetiracetam, in a three‐way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEV_CIR and LEV_CER were 50.72 ± 10.60 and 53.58 ± 15.94 μg/ml, respectively. The y ‐intercept for IV administration was 64.54 ± 24.99 μg/ml. The terminal half‐life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEV_CIR , LEV_{CER ,} and LEV_IV , respectively. Volume of distribution at steady‐state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg^?1 hr^?1. Bioavailability was 96 ± 10, and 98 ± 13% for LEV_CIR and LEV_CER , respectively. A single dose of Levetiracetam (LEV ) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.     

Postoperative pharmacokinetics of meloxicam in horses after surgery for colic syndrome

NSAID s are often used in horses with colic syndrome during the postoperative period, due to their ability to contrast endotoxemia and to promote an analgesic and anti‐inflammatory effect. As the pharmacokinetics of a drug are often modified in unhealthy animals compared to healthy subjects, the aim of this study was to evaluate the pharmacokinetic profile of meloxicam after i.v. administration in horses undergoing laparotomy for colic syndrome. Eight horses received 0.6 mg/kg of meloxicam i.v. towards the end of surgery. Blood samples were taken at scheduled time points during the following 24 hr. The serum concentration of the drug was determined by HPLC . Terminal half‐life (6.88 ± 2.96 hr), volume of distribution at steady‐state (186.53 ± 61.20 ml/Kg) and clearance (27.91 ± 5.72 ml kg^?1 hr^?1) were similar to those reported in literature for healthy horses. This result suggests that no adjustment of the approved dose should be necessary when meloxicam is used to treat horses in the immediate postoperative period after surgery for colic syndrome.     

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.     

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 florfenicol and its metabolite,florfenicol amine,in rice field eel (Monopterus albus) after a single‐dose intramuscular or oral administration

The pharmacokinetics of florfenicol (FF) and its metabolite, florfenicol amine (FFA), were studied in rice field eel (Monopterus albus) after a single dose (20 mg/kg) by intramuscular (i.m.) or oral gavage (p.o.) dose at 25 °C. The elimination half‐lives (t_1/2β), peak concentration of FF (C_max), and time to reach FF peak concentration (T_max) in plasma were estimated as 18.39 h, 10.83 μg/mL, and 7.00 h, respectively, after i.m. injection and 13.46 h, 8.37 μg/mL, and 5 h, respectively, after p.o. administration. The T_max values of FF in tissues (i.e., kidney, muscle, and liver) were larger for i.m. injection compared with those for p.o. administration. The t_1/2β had the following order kidney > muscle > liver for i.m. administrated and kidney > liver > muscle for p.o. administrated. The largest area under the concentration–time curve (AUC) was calculated to be 384.29 mg · h/kg after i.m. dosing, and the mean residence time (MRT) was 42.46 h by oral administration in kidney. FFA was also found in all tissues with a lower concentration than FF for both i.m. and p.o. administrations throughout the study. The elimination of FFA was slow with a t_1/2β between 18.19 and 47.80 h in plasma and tissues. The mean metabolic rate of FFA for i.m. and p.o. administrations was >23.30%.     

Sedative effects of hydromorphone or oxymorphone with or without acepromazine in dogs

Hydromorphone is an agonist opioid with potency approximately five times that of morphine and half that of oxymorphone. The purpose of this study was to compare hydromorphone with oxymorphone, with or without acepromazine, for sedation in dogs, and to measure plasma histamine before and after drug administration. Ten dogs received IM hydromorphone (H; 0.2 mg kg^?1), oxymorphone (O; 0.1 mg kg^?1), hydromorphone with acepromazine (H; 0.2 mg kg^?1, A; 0.05 mg kg^?1) or oxymorphone with acepromazine (O; 0.1 mg kg^?1, A; 0.05 mg kg^?1) in a randomized Latin‐square design. Sedation score, heart rate, respiratory rate, blood pressure, and SpO₂ were recorded at baseline and every 5 minutes after drug administration up to 25 minutes. Plasma histamine was measured at baseline and at 25 minutes post‐drug administration. Data were analyzed with repeated measures anova . Mean ± SD body weight was 21.62 ± 1.54 kg. Mean ± SD age was 1.07 ± 0.19 years. Sedation score was significantly greater for OA after 5 minutes than O alone (4.1 ± 3.5 versus 1.9 ± 1.5) and for HA after 15 minutes than H alone (8.6 ± 2.9 versus 5.9 ± 2.5). There was no significant difference in sedation between H and O at any time point. There was no significant difference between groups at any time with respect to heart rate, respiratory rate, blood pressure or SpO₂. Mean ± SD plasma histamine (nM ml^?1) for all groups was 1.72 ± 2.69 at baseline and 1.13 ± 1.18 at 25 minutes. There was no significant change in plasma histamine concentration in any group. Hydromorphone is effective for sedation in dogs and does not cause measurable increase in histamine. Sedation with hydromorphone is enhanced by acepromazine.     

Dosage assessment of valnemulin in pigs based on population pharmacokinetic and Monte Carlo simulation

To estimate the valnemulin pharmacokinetic profile in a swine population and to assess a dosage regimen for increasing the likelihood of optimization. This study was, respectively, performed in 22 sows culled by p.o. administration and in 80 growing‐finishing pigs by i.v. administration at a single dose of 10 mg/kg to develop a population pharmacokinetic model and Monte Carlo simulation. The relationships among the plasma concentration, dose, and time of valnemulin in pigs were illustrated as C_i,v = X₀(8.4191 × 10^‐4 × e^?0.2371t + 1.2788 × 10^?5 × e^?0.0069t) after i.v. and C_p.o = X₀(?8.4964 × 10^?4 × e^?0.5840t + 8.4195 × e^?0.2371t + 7.6869 × 10^?6 × e^?0.0069t) after p.o. Monte Carlo simulation showed that T_>MIC was more than 24 h when a single daily dosage at 13.5 mg/kg BW in pigs was administrated by p.o., and MIC was 0.031 mg/L. It was concluded that the current dosage regimen at 10–12 mg/kg BW led to valnemulin underexposure if the MIC was more than 0.031 mg/L and could increase the risk of treatment failure and/or drug resistance.     

A study of the pharmacokinetics and thromboxane inhibitory activity of a single intramuscular dose of carprofen as a means to establish its potential use as an analgesic drug in white rhinoceros

The alleviation of pain and prevention of suffering are key aspects of animal welfare. Unfortunately, analgesic drugs are not available for all species. White rhinoceros (Ceratotherium simum ), representing one of such species, which survive poaching attempts inflicted with severe facial injuries and gunshot wounds, nonetheless require analgesic support. To improve treatment conditions, this study explored the use of carprofen for the treatment of pain and inflammation in white rhinoceros. The pharmacokinetics of 1 mg/kg intramuscular carprofen was evaluated in six healthy white rhinoceros. The half‐life of λ_z and mean residence time was 105.71 ± 15.67 and 155.01 ± 22.46 hr, respectively. The area under the curve and the maximum carprofen concentration were 904.61 ± 110.78 μg ml^?1 hr^?1 and 5.77 ± 0.63 μg/ml, respectively. Plasma TXB ₂ inhibition demonstrated anti‐inflammatory properties and indicated that carprofen may be effective for a minimum of 48 hr in most animals. With its long half‐life further indicating that a single dose could be effective for several days, we suggest that carprofen may be a useful drug for the treatment of white rhinoceros.     

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t‐TUCB in horses with experimentally induced radiocarpal synovitis

This study determined the pharmacokinetics, antinociceptive, and anti‐inflammatory effects of the soluble epoxide hydrolase (sEH ) inhibitor t ‐TUCB (trans ‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid) in horses with lipopolysaccharide (LPS )‐induced radiocarpal synovitis. A total of seven adult healthy mares (n  = 4–6/treatment) were administered 3 μg LPS into one radiocarpal joint and t ‐TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 hr after t ‐TUCB /LPS . Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF ) t ‐TUCB concentrations were determined before and up to 48 hr after t ‐TUCB /LPS . Blood and SF were collected for clinical laboratory evaluations before and up to 48 hr after t ‐TUCB /LPS . Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post‐test. p  < .05 was considered significant. Data are mean ± SEM . Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t ‐TUCB , but not the other doses. For 0.1, 0.3, and 1 mg/kg t ‐TUCB treatments, plasma terminal half‐lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr^?1 kg^?1. The 1 mg/kg t ‐TUCB reached the SF at high concentrations. There were no important anti‐inflammatory effects. In conclusion, sEH inhibition with t ‐TUCB may provide analgesia in horses with inflammatory joint pain.     

Disposition Kinetics of Difloxacin After Intravenous,Intramuscular and Subcutaneous Administration in Calves

The pharmacokinetics of difloxacin (Dicural) was studied in a crossover study using three groups (n = 4) of male and female Friesian calves after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations of 5 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography using fluorescence detection. The plasma concentration–time data following i.v. administration were best fitted to a two-compartment open model and those following i.m. and s.c. routes were best fitted using one-compartment open model. The collected data were subjected to a computerized kinetic analysis. The mean i.v., i.m. and s.c. elimination half-lives (t _1/2β) were 5.56 ± 0.33 h, 6.12 ± 0.42 h and 7.26 ± 0.6 h, respectively. The steady-state volume of distribution (V _dss) was 1.12 ± 0.09 L/kg and total body clearance (Cl_B) was 2.19 ± 0.1 ml/(min. kg). The absorption half lives (t _1/2ab) were 0.38 ± 0.027 h and 2.1 ± 0.09 h, with systemic bioavailabilities (F) of 96.5% ± 6.4% and 84% ± 5.5% after i.m. and s.c. administration, respectively. After i.m. and s.c. dosing, peak plasma concentrations (C _max) of 3.38 ± 0.13 μg/ml and 2.18 ± 0.12 μg/ml were attained after (t _max) 1.22 ± 0.20 h and 3.7 ± 0.52 h. The MIC₉₀ of difloxacin for Mannheimia haemolytica was 0.29 ± 0.04 μg/ml. The AUC/MIC₉₀ and C _max/MIC₉₀ ratios for difloxacin following i.m. administration were 120 and 11.65, respectively and following s.c. administration were 97.58 and 7.51, respectively. Difloxacin was 31.7–36.8% bound to calf plasma protein. Since fluoroquinolones display concentration-dependent activities, the doses of difloxacin used in this study are likely to involve better pharmacodynamic characteristics that are associated with greater clinical efficacy following i.m. administration than following s.c. administration.