Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

BACKGROUND: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. OBJECTIVES: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. METHODS: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. RESULTS: The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. CONCLUSIONS: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.

Research Note: Pharmacokinetics of bromhexine hydrochloride in broilers after single oral and intravenous administration.

The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.

Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg.

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 d for intravenous treated and for 40 d from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Noncompartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 d for intravenous and 14.3 d for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 d and 81 d, respectively, with maximum residue limits (1.3 µg/g) at 13 d and 171 d, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA.

Pharmacokinetics of tildipirosin in estuarine (Crocodylus porosus) and freshwater (Crocodylus siamensis) crocodiles.

Tildipirosin is a macrolide antimicrobial. It is authorised for the treatment and prevention of respiratory disease in cattle and pigs. There are no data on its administration in crocodiles. Therefore, this study evaluated the disposition kinetics of tildipirosin after intravenous (dose: 2 mg/kg) and intramuscular (doses: 2 and 4 mg/kg) administration in two crocodilian species (estuarine and freshwater; n = 5). Tildipirosin plasma concentrations were quantified by a validated HPLC method. Plasma concentrations obtained at each extraction time were analysed by non-compartmental methods. In the estuarine and freshwater crocodiles, the apparent volumes of distribution of tildipirosin after intravenous administration were 0.36 ± 0.10 and 1.48 ± 0.26 L/kg, respectively. These values, suggesting poorer tissue distribution, were much lower than those obtained in mammals. There was complete bioavailability of tildipirosin after intramuscular route at a dose of 2 mg/kg; however, at a dose of 4 mg/kg the bioavailability decreased by about 20-25 %. Furthermore, the pharmacokinetics of tildipirosin were markedly different in the two crocodilian species. Considering a MIC of 0.5 µg/mL, the surrogate marker AUC0-24/MIC indicates that tildipirosin would greatly exceed the value of 65 h for both crocodile species and dose levels tested. This suggests that both doses (2 and 4 mg/kg) may provide a bactericidal effect. Therefore, based on the absence of adverse reactions following the administration of tildipirosin in both crocodilian species, and considering its favourable pharmacokinetic properties, tildipirosin may be useful in treating infections in these reptiles.

Comparative pharmacokinetics of intravenous and subcutaneous pantoprazole in sheep and goats.

Abomasal ulcers are a significant concern in intensive animal farming due to their impact on animal health and productivity. While proton pump inhibitors (PPIs) such as pantoprazole (PTZ) show promise in treating these ulcers, data on PTZ's pharmacokinetics (PK) in adult goats and sheep are limited. This study aims to fill this gap by investigating and comparing PTZ's PK in these species following single intravenous (IV) and subcutaneous (SC) administrations. Five healthy male goats and sheep were included in the study. PTZ concentrations in plasma samples were determined using a validated analytical method. Non-compartmental analysis was conducted, and statistical comparisons were made between IV and SC administrations and between species. Sheep and goats showed similar systemic exposure levels regardless of the administration route. However, sheep had a shorter t1/2 due to a higher Vd compared to goats. Cl values were comparable in both species, with low extraction ratio values. There were no significant differences in Cmax and Tmax between the two species with regards to SC administration, and complete bioavailability was observed. The MAT exceeded the t1/2 in both species, indicating a potential flip-flop phenomenon. Considering the AUC as a predictor for drug efficacy, and observing no significant differences in systemic exposure between sheep and goats for any route of administration, dosage adjustment between the two species may not be necessary. In field settings, SC administration proves more practical, providing not only complete bioavailability but also a longer half-life compared to IV. Further studies are warranted to explore the PK/PD of PTZ in small ruminants with abomasal ulcers, to fully comprehend its therapeutic efficacy in such scenarios.

Pharmacokinetics of amikacin after intravenous, intra-articular, and combined intravenous and intra-articular administration in healthy neonatal foals.

BACKGROUND: Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration. HYPOTHESIS/OBJECTIVES: Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. ANIMALS: Eight healthy neonatal foals. METHODS: Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 µg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. RESULTS: Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean µg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.

Effect of a single intravenous injection of branched chain amino acids on body temperature of cats undergoing general anesthesia.

OBJECTIVE: To evaluate the effect of a single intravenous injection of branched chain amino acids (BCAAs) on body temperature in cats undergoing general anesthesia. STUDY DESIGN: Prospective, blinded, randomized, crossover, experimental study. ANIMALS: A total of 10 healthy adult cats (five female and five male). METHODS: Cats were anesthetized three times with three different treatments in a random order: 3 mL kg-1 lactated Ringer's solution (LRS), 100 mg kg-1 BCAAs (B100) or 200 mg kg-1 BCAAs (B200) solution immediately before induction of anesthesia. After induction, rectal temperature was measured every 5 minutes. Blood samples were collected for the measurement of blood glucose (BG) just before induction, at the end of the 90 minute period of anesthesia, and 24 hours after anesthesia induction. The differences between baseline and each subsequent rectal temperature, and BG measurements were analyzed. Areas under the curve (AUCs) for temperature differences were calculated for each animal for the anesthetic period (AUCT0-90). Parametric or nonparametric data were analyzed by one-way repeated measures anova or Friedman test. A value of p < 0.05 was considered significant. RESULTS: There were no significant differences in AUCT0-90 between groups: 41.6 ± 7.7 for LRS, 43.4 ± 6.9 for B100 and 42.9 ± 7.5 for B200 (p = 0.368). No significant differences were observed in BG between groups at 90 minutes and 24 hours after anesthesia induction (p = 0.283 and p = 0.089, respectively). The incidence of hypoglycemia [BG ≤ 3.17 mmol L-1 (57 mg dL-1)] after anesthesia tended to be higher in both B100 (4/10 cats) and B200 groups (3/10 cats) than in LRS group (1/10 cats). CONCLUSIONS AND CLINICAL RELEVANCE: A single, preanesthetic intravenous injection of BCAAs did not attenuate heat loss during anesthesia. More cats were hypoglycemic in the BCAA groups than in the LRS group.

Plasma pharmacokinetics of clorsulon following administration of a single subcutaneous or intravenous injection to cattle.

The benzenedisulfonamide derivative clorsulon is a potent fasciolicide which is marketed in fixed combination injectables, typically combined with the macrocyclic lactone ivermectin. In the presented pharmacokinetic study, the plasma profile of clorsulon in 32 healthy, young Brown Swiss cattle was administered a single intravenous dose at 3 mg/kg body weight or subcutaneously at 3, 6 or 12 mg/kg body weight (4 intact male and 4 female animals per treatment) as a 30% w/v clorsulon injection formulation. Serial blood samples were collected up to 24 days after administration to establish the pharmacokinetics, bioavailability and dose proportionality of clorsulon. Following a single intravenous injection of clorsulon at 3 mg/kg body weight, the area under the concentration versus time curve from the start of dose administration to the time of the last quantifiable concentration (AUClast ) was 4830 ± 941 day*ng/mL, and half-live was 2.37 ± 0.98 days. The back extrapolated concentration at time 0 was 38,500 ± 6070 ng/mL. The volume of distribution at steady state and clearance were 685 ± 107 mL/kg and 664 ± 127 mL/day/kg, respectively. In the groups dosed at 3, 6 or 12 mg/kg body weight by subcutaneous injection, clorsulon plasma concentrations rose to maximum within 0.5 day and decreased to the last sample point. For these groups, the maximum plasma clorsulon concentrations were 3100 ± 838, 5250 ± 1220 and 10,800 ± 1730 ng/mL, respectively, and the AUClast was 5330 ± 925, 9630 ± 1300 and 21,500 ± 3320 day*ng/mL, respectively. Half-lives, 2.01 ± 0.62, 3.84 ± 1.42 and 5.36 ± 0.60 days, respectively, increased significantly with dose, likely related to increasing dose volume. Clorsulon was well absorbed and fully bioavailable (103%-114%) after subcutaneous injection. No gender-related difference in systemic exposure was observed. Assessment of Cmax and AUClast demonstrated a proportional increase in systemic exposure to the clorsulon subcutaneous doses over the range of 3-12 mg/kg body weight.

Characterisation of the pruritus responses and pruritic behaviours in an interleukin 31-induced canine model of pruritus.

BACKGROUND: Intravenous administration of interleukin (IL)-31 in healthy dogs has been used as a model to assess antipruritic drugs. However, there is no known in-depth characterisation of pruritic behaviours, and the repeatability of the IL-31-induced pruritus in the individual dogs is currently unknown. OBJECTIVES: To evaluate the immediate/delayed pruritus responses and the pruritic behaviours observed in the IL-31-induced pruritic model in healthy dogs after repeated IL-31 injections. ANIMALS: Fifteen healthy laboratory beagles. METHODS: All dogs were video-recorded for 270 min after two intravenous recombinant IL-31 injections (1.75 µg/kg) and vehicle (phosphate-buffered saline, control) injections, respectively; interventions were randomised and performed with a 2 week wash-out period. Two blinded investigators reviewed the pruritic behaviours of all video recordings. RESULTS: Both canine IL-31 (IL-31_01, IL-31_02) injections significantly increased pruritic seconds and categorical minutes ('YES'/'NO' behaviour per discrete 1 min interval) in healthy dogs compared with both vehicle groups (Vehicle_01, Vehicle_02). The second intravenous canine IL-31 (IL-31_02) administered 14 days after the first IL-31 injection induced a significant increase in pruritic seconds (p = 0.021) and not pruritic categorical minutes (p = 0.231). An increase in pruritic seconds was observed in both IL-31 groups in the first 30 min post-administration, while there was no significant difference between IL-31 and vehicle groups. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, intravenous IL-31 reproducibly induces itch responses in dogs. Future evaluations of the canine IL-31 pruritic model should assess total pruritic behaviours in seconds rather than using a biased 'YES/NO' behaviour per 1 min scoring system.

Pharmacokinetics of hydrorphone hydrochloride after intravenous and subcutaneous administration in ferrets (Mustela putorius furo).

OBJECTIVE: To determine the pharmacokinetic profile of hydromorphone 0.2 mg kg-1 administered by the intravenous (IV) and subcutaneous (SC) route in ferrets. STUDY DESIGN: Randomized, crossover study. ANIMALS: A group of eight adult ferrets weighting (mean ± standard deviation) 1.02 ± 0.22 kg. METHODS: Hydromorphone hydrochloride 0.2 mg kg-1 was administered IV or SC with a washout period of 7 days. Blood samples were collected from a jugular catheter before administration of hydromorphone and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 minutes after hydromorphone administration. Plasma hydromorphone concentrations were determined by liquid chromatography/tandem mass spectrometry. Data were analyzed using a non-linear mixed effects model. RESULTS: The hydromorphone effective half-life was (t1/2) 45 min-1. Systemic clearance (Cls) and the volume of distribution (Vdss) following IV administration were 84.8 mL kg-1 min-1 and 5.59 L kg-1, respectively. The maximum observed plasma concentration was 59.53 ± 14.02 ng mL-1 within 10 minutes following SC administration. The SC bioavailability was 102.0%. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of IV and SC hydromorphone (0.2 mg kg-1) was characterized by a high clearance, short terminal half-life and large volume of distribution. Hydromorphone plasma concentrations remained greater than 2 ng mL-1 for 2 hours in most ferrets, a threshold reported to provide antinociceptive effects in other species. Hydromorphone was well absorbed following SC injection, providing an alternative administration route for clinical use in ferrets.

Population pharmacokinetic analysis of enrofloxacin and its active metabolite ciprofloxacin after intravenous injection to cats with reduced kidney function.

BACKGROUND: It is unknown if enrofloxacin accumulates in plasma of cats with reduced kidney function. HYPOTHESIS: To determine if enrofloxacin and its active metabolite ciprofloxacin have reduced clearance in azotemic cats. ANIMALS: Thirty-four cats hospitalized for clinical illness with variable degree of kidney function. METHODS: Prospective study. After enrofloxacin (dose 5 mg/kg) administration to cats, sparse blood sampling was used to obtain 2 compartment population pharmacokinetic results using nonlinear mixed-effects modeling. Plasma enrofloxacin and ciprofloxacin concentrations were measured and summed to obtain the total fluoroquinolone concentration. A model of ciprofloxacin metabolism from enrofloxacin was created and evaluated for covariate effects on clearance, volume of distribution, and the metabolic rate of ciprofloxacin generation from enrofloxacin. RESULTS: Body weight was the only covariate found to affect total fluoroquinolone volume of distribution (effect 1.63, SE 0.19, P < .01) and clearance (effect 1.63, SE 0.27, P < .01). Kidney function did not have a significant effect on total fluoroquinolone clearance (median 440.8 mL/kg/h (range 191.4-538.0 mL/kg/h) in cats with normal kidney function, 365.8 mL/kg/h (range 89.49-1092.0 mL/kg/h) in cats with moderate kidney dysfunction, and 308.5 mL/kg/h (range 140.20-480.0 mL/kg/h) in cats with severe kidney dysfunction (P = .64). Blood urea nitrogen concentration influenced the metabolic generation of ciprofloxacin from enrofloxacin (effect 0.51, SE 0.08, P < .01), but other markers of kidney function did not. CONCLUSIONS AND CLINICAL IMPORTANCE: Adjustment of enrofloxacin dosage is not indicated for azotemic cats.

Biliary excretion and pharmacokinetics of several fluoroquinolones after intravenous injection in rabbits.

The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin (OFLX) in the plasma and bile of rabbits after a single intravenous (IV) injection. Twenty male rabbits were divided into four groups and given each drug by IV injection into the ear vein at a dose of 5.0 mg/kg BW. The concentration of ERFX, ciprofloxacin (CPFX), OBFX, MBFX and OFLX in plasma and bile were determined by HPLC. CPFX, metabolite of ERFX, was also measured by HPLC in plasma and bile of rabbits receiving ERFX. Several pharmacokinetic parameters in plasma were calculated and biliary clearance (CLbile) was calculated from extent of biliary excretion and accumulation of AUC of each drug. After IV injection, elimination half-life (t1/2ß) was 4.13, 3.68, 6.60, 5.14 hr; volume of distribution at a steady state (Vdss) was 1.24, 0.503, 0.771, 1.02 L/kg; and total body clearance (CLtot) was 1.05, 0.418, 0.271, 0.453 L/kg/hr, respectively. The values for CLbile for ERFX, OBFX, MBFX, and OFLX were 0.0048, 0.0050, 0.0057, and 0.0094 L/kg/hr, respectively. These values represent 0.48%, 1.2%, 2.1%, and 2.3% of the total body clearance (CLtot) of each drug, respectively. The biliary clearance of CPFX was also measured and found to be 0.0199 L/kg/hr with ERFX administration. The results showed that ERFX, OBFX, MBFX, and OFLX were not excreted into the bile to a significant extent, making them safe drugs to use in rabbits.

Pharmacokinetics and bioavailability of meloxicam in Pekin ducks following intravenous, intramuscular and oral administration.

OBJECTIVE: To determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg-1 in Pekin ducks. STUDY DESIGN: Randomized experimental trial. ANIMALS: A total of 18 clinically healthy male Pekin ducks. METHODS: Pekin ducks were randomly assigned to three groups of six ducks: IV, IM and oral. Meloxicam (1.0 mg kg-1) was administered to each Pekin duck. A non-compartmental analysis was used to evaluate pharmacokinetic parameters. RESULTS: No local or systemic adverse effects were observed in any bird. Meloxicam was detected in the plasma up to 120 hours following IV, IM or oral administration. The elimination half-life of the IV route was slightly shorter than that of the IM and oral routes (p < 0.05). Following IV administration, volume of distribution at steady state and total clearance were 133.17 mL kg-1 and 6.68 mL kg-1 hour-1, respectively. The mean absorption time was 2.29 hours for IM and 1.13 hours for oral route. There were significant differences between IM and oral administration for the peak plasma concentration (Cmax), time to reach Cmax and bioavailability (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam showed long elimination half-life and high bioavailability following IM and oral administration. Meloxicam in Pekin ducks provided the effective therapeutic concentration indicated in other species for up to 48 hours. However, there is a need to determine the clinical efficacy of meloxicam in Pekin ducks.

Age-related changes in the pharmacokinetics of meloxicam after intravenous administration in sheep.

The pharmacokinetics of meloxicam was studied in 1-, 6-, and 12-month-old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 ± 0.91 kg), 6 months old (27.47 ± 4.91 kg), and 12 months old (37.10 ± 3.64 kg). Meloxicam concentration in plasma was determined by high-performance liquid chromatography and the data collected were evaluated by non-compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (Vdss ) and total body clearance (ClT ) were significantly higher in 1-month-old (304.87 mL/kg and 16.57 mL/h/kg) than in 12-month-old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration-time curve from 0 to 72 h value of meloxicam was lower in 1-month-old (58.51 h*µg/mL) compared to 12-month-old (92.59 h*µg/mL) sheep. There was no difference in t1/2ʎz value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in Vdss and ClT in 12-month-old compared to 1-month-old sheep. Compared to 1-month-old and 12-month-old sheep, there was no difference in these parameters in 6-month-old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age.

Pharmacokinetics of meloxicam in pigeons after single intravenous, oral, and intramuscular administration.

This study aimed to determine the pharmacokinetics of meloxicam in pigeons. Twenty-four 7-wk-old meat pigeons (Columba livia) were randomly divided into 3 groups (PO, IM, and IV) and given a single dose of 1 mg/kg body weight of meloxicam. Plasma samples were taken at predetermined times, which were then analyzed using a validated high-performance liquid chromatography (HPLC) method and subjected to noncompartmental analysis using Phoenix software. Results indicated that meloxicam was absorbed effectively and quickly after PO and IM dosing. Peak concentrations (0.83 ± 0.21 and 1.59 ± 0.49 µg/mL) were achieved at 2 and 0.26 h, respectively, with mean absorption times of 2.56 ± 1.50 and 1.47 ± 0.89 h. Bioavailability was high at 86.31 ± 43.45% and 81.57 ± 52.58%, respectively, and the area under the concentration-time curve (AUC0-∞) was 5.33 ± 2.68 and 5.03 ± 3.26 h·µg/mL. After IV administration, the elimination was faster with a total body clearance (CL) of 188.75 ± 83.23 mL/h/kg, an elimination half-life (t1/2λz) of 1.76 ± 0.56 h, and a volume of distribution at steady-state (VSS) of 427.50 ± 188.43 mL/kg. Considering the lack of a precise analgesic threshold of meloxicam in pigeons and the notable differences in its analgesic threshold among various animal species, formulating a dosing regimen in pigeons presented a significant challenge. Based on the previous analgesic threshold (3.5 µg/mL) in parrots, a higher dose (e.g., 2 mg/kg) or shorter dosing interval (e.g., every 6 h) is recommended for treating pain in pigeons. Nonetheless, further pharmacodynamic research is required to verify these recommendations.

Disposition kinetics of robenacoxib following intravenous and oral administration in geese (Anser anser domesticus).

Robenacoxib (RX) is a veterinary cyclooxygenase-2 selective inhibitor drug. It has never been tested on birds and is only labelled for use in cats and dogs. The purpose of this study was to assess its pharmacokinetics in geese after single intravenous (IV) and oral (PO) administrations. Four-month healthy female geese (n = 8) were used. Geese were subjected to a two-phase, single-dose (2 mg/kg IV, 4 mg/kg PO), open, longitudinal study design with a four-month washout period between the IV and the PO phases. Blood was collected from the left wing vein to heparinized tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24 h. Plasma RX concentrations were measured using HPLC coupled to an UV detector, and the data were pharmacokinetically analysed using ThothPro™ 4.3 software in a non-compartmental approach. Following IV administration, terminal elimination half-life, volume of distribution, and total clearance were 0.35 h, 0.34 L/kg, and 0.68 L/h/kg, respectively. For the PO route, the mean peak plasma concentration was 6.78 µg/mL at 0.50 h. The t1/2λz was very short and significantly different between the IV and PO administrations (0.35 h IV vs. 0.99 h PO), suggesting the occurrence of a flip-flop phenomenon. The Cl values corrected for the F% were significantly different between IV and PO administrations. It might have been a consequence of the longitudinal study design and the altered physiological and environmental conditions after a 4-month washout period. The absolute oral F% computed with the AUC method surpassed 150%, but after normalizing it to t1/2λz, it was 46%. In conclusion, the administration of RX might not be suitable for geese, due to its short t1/2λz.

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus).

OBJECTIVE: To determine the pharmacokinetic parameters of hydromorphone hydrochloride and its metabolite, hydromorphone-3-glucuronide (H3G), after a single IV and IM dose in great horned owls (Bubo virginianus). ANIMALS: 6 healthy adult great horned owls (3 females and 3 males). PROCEDURES: A single dose of hydromorphone (0.6 mg/kg) was administered once IM (pectoral muscles) and IV (left jugular) with a 6-week washout period between experiments. Blood samples were collected at 5 minutes and 0.5, 1.5, 2, 3, 6, 9, and 12 hours after drug administration. Plasma hydromorphone and H3G concentrations were determined with liquid chromatography-tandem mass spectrometry, and a noncompartmental analysis was used for the determination of pharmacokinetic parameters. RESULTS: Hydromorphone had a high bioavailability of 170.8 ± 37.6% and rapid elimination after IM administration and rapid plasma clearance and a large volume of distribution after IV administration. Mean Cmax was 225.46 ± 0.2 ng/mL at 13 minutes after IM injection. Mean volume of distribution and plasma drug clearance was 4.29 ± 0.5 L/kg and 62.11 ± 14.6 mL/min/kg, respectively, after IV administration. Mean t1/2 was 1.62 ± 0.36 and 1.35 ± 0.59 hours after IM and IV administration, respectively. The metabolite H3G was readily measured shortly after administration by both routes. CLINICAL RELEVANCE: A single dose of 0.6 mg/kg was well tolerated in all birds. Hydromorphone rapidly attained plasma concentrations following IM administration and had high bioavailability and short t1/2. This study is the first to document the presence of the metabolite H3G in avian species, which suggests similar hydromorphone metabolism as in mammals.

Pharmacokinetic profiles of the two major active metabolites of metamizole, 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA), after intravenous injection in cats.

This study aimed to determine the pharmacokinetic profile of two active metabolites of metamizole (dipyrone), N-methyl-4-aminoanthypyrine (MAA) and 4-aminoanthypyrine (AA), after intravenous administration in cats. Eight healthy mixed-breed cats were intravenously administered metamizole (25 mg/kg). Blood samples were collected at predetermined time points for up to 48 h after administration. Information on behavioral changes in the animals and adverse effects was collected. Plasma aliquots were processed and analyzed using the ultra-performance liquid chromatography tandem mass spectrometry technique. A validated UPLC-MS/MS method was used to characterize the pharmacokinetics of MAA and AA. Salivation was identified as an adverse clinical sign. The mean maximal plasma concentrations of MAA and AA were 29.31 ± 24.57 µg/mL and 1.69 ± 0.36 µg/mL, with half-lives of around 4.98 and 14 h, respectively. The area under the plasma concentration curve values were 28.54 ± 11.33 and 49.54 ± 11.38 h*µg/mL for MAA and AA, respectively. The plasma concentration of MAA was detectable for up to 24 h and was smaller than AA. AA was detectable for >48 h. Results suggest that metamizole is converted into active metabolites in cats. Further PK/PD and safety studies should be performed before defining the dose or administration intervals for clinical use.

Comparative pharmacokinetics of florfenicol in heifers after intramuscular and subcutaneous administration.

Florfenicol was administered to five heifers intramuscularly at a dose rate of 20 mg/kg bwt and following wash-out period, subcutaneously at a dose rate of 40 mg/kg bwt. Blood plasma samples were collected from heifers before injection of florfenicol and up to 120 h after intramuscular (IM) injection and up to 264 h after subcutaneous (SC) injection. Florfenicol concentrations in plasma were measured by high-performance liquid chromatography with mass-spectrometric detection. Pharmacokinetics of florfenicol was estimated using non-compartment analysis. Mean maximum plasma concentration, area under the concentration-time curve and elimination half-life for florfenicol were 3.2 µg/ml, 101.5 µg × h/ml and 24.5 h, respectively, after IM injection at 20 mg/kg bwt, and 2.7 µg/ml, 194.5 µg × h/ml and 103.8 h, respectively, after SC injection at 40 mg/kg bwt. The obtained results indicated that both administration routes provided comparable bioavailability, whereas SC route was attributed with lower peak levels and markedly slower absorption of florfenicol from injection site. Both administration routes provided plasma florfenicol levels which are expected to be effective against prevalent infectious agents of cattle.