Comparative Pharmacokinetics of Intravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep.

BACKGROUND: Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target- age animals. OBJECTIVE: To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. METHODS: The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC-UV and analyzed using a non-compartmental method. RESULTS: ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep. CONCLUSION: The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0-24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after intravenous administration of increasing doses to sheep.

OBJECTIVE: To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. ANIMALS: 6 healthy adult Merino sheep. PROCEDURES: Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. RESULTS: No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h·µg/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep.

Pharmacokinetics of intravenous and intramuscular danofloxacin in red-eared slider turtles (Trachemys scripta elegans).

This study aimed to investigate the pharmacokinetics of danofloxacin in red-eared slider turtle (Trachemys scripta elegans) following a single intravenous (IV) and intramuscular (IM) administrations of 6 mg/kg, using a two-way crossover study with 30-day washout period. Eight clinically healthy red-eared slider turtle weighing 410-600 g (mean 490 g) were used for the study. Danofloxacin concentrations were measured using the reversed-phase high-performance liquid chromatography. The plasma concentration-time data were evaluated by a non-compartmental method. After IV administration, the elimination half-life (t1/2ʎz), mean residence time (MRT0-∞), area under the concentration-time curve (AUC0-∞), volume of distribution at steady state and total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr·µg/ml, 1.29 l/kg and 0.04 l/hr/kg, respectively. Following IM administration, t1/2ʎz, MRT0-∞, AUC0-∞, peak concentration (Cmax), time to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr·µg/ml, 8.75 µg/ml, 1.5 hr and 139.89%, respectively. Danofloxacin has clinically superior pharmacokinetic properties, including the complete IM absorption, slow elimination and wide volume of distribution in red-eared slider turtles. However, further pharmacokinetics/pharmacodynamics studies are necessary for the treatment of diseases caused by susceptible bacteria with known minimum inhibitory concentration values in red-eared slider turtles.

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep.

The purpose of this study was to determine the pharmacokinetics of cefquinome (CFQ) following single and repeated subcutaneous (SC) administrations in sheep. Six clinically healthy, 1.5 ± 0.2 years sheep were used for the study. In pharmacokinetic study, the crossover design in three periods was performed. The withdrawal interval between the study periods was 15 days. In first period, CFQ (Cobactan, 2.5%) was administered by an intravenous (IV) bolus (3 sheep) and SC (3 sheep) injections at 2.5 mg/kg dose. In second period, the treatment administration was repeated via the opposite administration route. In third period, CFQ was administrated subcutaneously to each sheep (n = 6) at a dose of 2.5 mg/kg q. 24 hr for 5 days. Plasma concentrations of CFQ were measured using the HPLC-UV method. Pharmacokinetic parameters were calculated using non-compartmental methods. The elimination half-life and mean residence time of CFQ after the single SC administration were longer than IV administration (p < 0.05). Bioavailability (F%) of CFQ following the single SC administration was 123.51 ± 11.54%. The area under the curve (AUC0-∞ ) and peak concentration following repeated doses (last dose) were higher than those observed after the first dose (p < 0.05). CFQ accumulated after repeated SC doses. CFQ can be given via SC at a dose of 2.5 mg/kg every 24 hr for the treatment of infections caused by susceptible pathogens, which minimum inhibitory concentration is ≤1.0 µg/ml in sheep.

Pharmacokinetics and bioavailability of tolfenamic acid in sheep.

The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC0-∞ ), elimination half-life (t1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.