Pharmacokinetic behaviour and pharmacokinetic-pharmacodynamic integration of doxycycline in rainbow trout (Oncorhynchus mykiss) after intravascular, intramuscular and oral administrations.

OBJECTIVE: Doxycycline (DO) has been used in fish for a long time, but there are some factors that have not yet been clarified regarding its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, the aim of this study was to investigate the PK and PK/PD targets of DO after 20 mg/kg intravascular (IV), intramuscular (IM) and oral (OR) gavage administration in rainbow trout (Oncorhynchus mykiss). METHODS: Plasma samples were collected at specific time points and subsequently analysed by HPLC-ultraviolet. The PK/PD indices were calculated based on the MIC90 (Aeromonas hydrophila and Aeromonas sobria) values obtained for the respective bacteria and the PK parameters obtained for DO following both IM and OR administration. RESULTS: After IV administration, the elimination half-life (t1/2 ʎz), area under the concentration vs. time curve (AUC), apparent volume of distribution at steady-state and total body clearance of DO were 34.81 h, 723.82 h µg/mL, 1.24 L/kg and 0.03 L/kg/h, respectively. The t1/2λz of the DO was found to be 37.39 and 39.78 h after IM, and OR administration, respectively. The bioavailability was calculated 57.02% and 32.29%, respectively, after IM and OR administration. The MIC90 of DO against A. hydrophila and A. sobria was 4 µg/mL. The PK/PD integration showed that DO (20 mg/kg dose) for A. hydrophila and A. sobria with MIC90 ≤4 µg/mL achieved target AUC/MIC value after IM administration. CONCLUSIONS: These results suggest that when rainbow trout was treated with 20 mg/kg IV and IM administered DO, therapeutically effective concentrations were reached in the control of infections caused by A. hydrophila and A. sobria.

Determination of temporal changes in hepatic drug-oxidizing capacity using plasma metabolite/caffeine ratios in non-pregnant and pregnant goats.

Caffeine (CF) is a metabolic probe drug used in the determination of the hepatic drug-oxidizing capacity. The aim of this study was to investigate temporal changes in the hepatic drug-oxidizing capacity using plasma metabolite/CF ratios in non-pregnant goats (n = 11) and pregnant goats (n = 23). CF (5 mg/kg, intravenous) was administered in six periods (Period 1-6) with 45 days between two periods. The plasma levels of CF and its metabolites, theophylline (TP), theobromine (TB) and paraxanthine (PX), were determined by HPLC-UV. To evaluate hepatic drug-oxidizing capacity in terms of enzymes that play a role in CF metabolism, the plasma metabolic ratios including TB/CF, PX/CF, TP/CF and TB + PX + TP/CF were determined at 10 h following CF administration. Plasma metabolite/CF ratios were similar between non-pregnant and pregnant goats. However, plasma metabolite/CF ratios in Period 3 (45 days in pregnant goats) were significantly higher than those other periods in both pregnant and non-pregnant goats. The effect of pregnancy may not be observed on drugs that are substrates of enzymes involved in CF metabolism in goats.

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, Tissue Residues, and Withdrawal Times of Oxytetracycline in Rainbow Trout (Oncorhynchus mykiss) after Single- and Multiple-Dose Oral Administration.

The aim of this study was to compare the pharmacokinetics of oxytetracycline (OTC) following single- (60 mg/kg) and multiple-dose oral administrations (60 mg/kg, every 24 h for 7 days) in rainbow trout. It also aimed to determine bioavailability after a single dose and tissue residues and withdrawal times after multiple doses. This study was carried out on 420 rainbow trout at 9 ± 0.8 °C. This study was carried out in two stages: single-dose (intravascular and oral) and multiple-dose treatment. The OTC concentrations in plasma and tissues were measured by high-performance liquid chromatography and analyzed by a non-compartmental method. The withdrawal time (WT) was estimated using the WT 1.4 software. OTC exhibited a long terminal elimination half-life (t1/2ʎz) after IV and oral administration. The oral bioavailability of OTC was very low (2.80%). In multiple-dose treatment, t1/2ʎz, the area under the plasma concentration-time curve and peak plasma concentration increased significantly after the last day compared to the first day. OTC showed strong accumulation after multiple doses with a value of 5.33. OTC concentrations were obtained in the order liver > kidney > muscle+skin > plasma. At 9 ± 0.8 °C, the WT calculated for muscle+skin was 56 days for Europe and 50 days for China, respectively. The t1/2ʎz (68.94 h) and time (68 h) above the 1 µg/mL MIC following a single OTC dose may support the extension of the 24 h dosing interval following multiple dosing. However, further studies are required to determine the optimal dosage regimen in multiple-dose OTC treatment in the treatment of infections caused by susceptible pathogens.

Pharmacokinetics of letrozole and effects of its increasing doses on gonadotropins in ewes during the breeding season.

Letrozole is a non-steroidal, third-generation aromatase inhibitor used in humans. Although letrozole is not approved for use in animals, it is used off-label in cases of synchronization and infertility. The aim of this study was to determine the pharmacokinetics of letrozole after a single intravenous administration at three different doses in ewes during the breeding season and its effect on gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) at the beginning of proestrus. The study was carried out on 24 healthy Merino ewes. Ewes were randomly divided into four groups (n = 6) as control, 0.5, 1, and 2 mg/kg. Plasma concentrations of letrozole were measured using HPLC-UV and were analyzed by non-compartmental analysis. LH and FSH concentrations were measured with a commercial ELISA kit. The terminal elimination half-life (t1/2ʎz ) was significantly prolonged from 11.82 to 18.44 h in parallel with the dose increase. The dose-normalized area under the concentration-time curve (AUC) increased, and total body clearance (ClT ) decreased at the 1 and 2 mg/kg doses (0.05 L/h/kg) compared with the 0.5 mg/kg dose (0.08 L/h/kg). There were no differences in the volume of distribution at steady-state and initial (C0.083h ) plasma concentration values between dose groups. The decreased ClT , prolonged t1/2ʎz, and increased AUC at increasing doses showed the nonlinear kinetic behavior of letrozole. Letrozole significantly reduced LH concentration without affecting FSH concentration at all doses. As a result, letrozole has the potential to be used in synchronization methods and manipulation of the follicular waves due to its effect on LH secretion.

Pharmacokinetics of meloxicam following intravenous administration at different doses in sheep.

The aim of this study is to determine the pharmacokinetic change after intravenous administration of meloxicam at doses of 0.5, 1 and 2 mg/kg to sheep. The study was carried out on six Akkaraman sheep. Meloxicam was administered intravenously to each sheep at 0.5, 1, and 2 mg/kg doses in a longitudinal pharmacokinetic design with a 15-day washout period. Plasma concentrations of meloxicam were determined using the high performance liquid chromatography-ultraviolet, and pharmacokinetic parameters were evaluated by non-compartmental analysis. Meloxicam was detected up to 48 h in the 0.5 mg/kg dose and up to 96 h in the 1 and 2 mg/kg doses. As the dose increased from 0.5 to 2 mg/kg, terminal elimination half-life, and dose normalized area under the concentration versus time curve increased and total clearance decreased. Compared to the 1 mg/kg dose, it was determined that Vdss decreased and C0.083h increased in the 2 mg/kg dose. Meloxicam provided the therapeutic concentration of >0.39 µg/mL reported in other species for 12, 48 and 96 h at 0.5, 1 and 2 mg/kg doses, respectively. These results show that meloxicam exhibits non-linear pharmacokinetics and will achieve unpredictable plasma concentrations when administered IV for a rapid effect at dose of ≥1 mg/kg in sheep.

Intestinal injury and vasculitis biomarkers in cats with feline enteric coronavirus and effusive feline infectious peritonitis.

OBJECTIVE: To investigate intestinal injury, repair and vasculitis biomarkers that may illuminate the progression and/or pathogenesis of feline infectious peritonitis (FIP) or feline enteric coronavirus (FECV) infection. MATERIALS AND METHODS: A total of 40 cats with effusive FIP (30 with abdominal effusion, AE group; 10 with thoracic effusion, TE group) and 10 asymptomatic but FECV positive cats (FECV group), all were confirmed by reverse transcription polymerase chain reaction either in faeces or effusion samples. Physical examinations and effusion tests were performed. Trefoil factor-3 (TFF-3), intestinal alkaline phosphatase (IAP), intestinal fatty acid binding protein (I-FABP), myeloperoxidase-anti-neutrophilic cytoplasmic antibody (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA) concentrations were measured both in serum and effusion samples. RESULTS: Rectal temperature and respiratory rate were highest in the TE group (p < 0.000). Effusion white blood cell count was higher in the AE group than TE group (p < 0.042). Serum TFF-3, IAP and I-FABP concentrations were higher in cats with effusive FIP than the cats with FECV (p < 0.05). Compared with the AE group, TE group had lower effusion MPO-ANCA (p < 0.036), higher IAP (p < 0.050) and higher TFF-3 (p < 0.016) concentrations. CLINICAL SIGNIFICANCE: Markers of intestinal and epithelial surface injury were higher in cats with effusive FIP than those with FECV. Compared to cats with abdominal effusions, markers of apoptosis inhibition and immunostimulation to the injured epithelium were more potent in cats with thoracic effusion, suggesting the possibility of a poorer prognosis or more advanced disease in these patients.

Effect of Xylazine on Pharmacokinetics and Physiological Efficacy of Intravenous Carprofen in Castrated Goats Kids.

Carprofen can be used in the castration process of male goats due to its low side effects, long elimination half-life, and long-term effect. However, no studies were found on the pharmacokinetics and physiological efficacy of carprofen when employed for castration in male goats. The aim of this study was to determine the effect of xylazine (0.05 mg/kg, intramuscular) on the pharmacokinetics and physiological efficacy following intravenous administration of carprofen (4 mg/kg, intravenous) in male goat kids castrated using the burdizzo method. Thirty male Kilis goat kids (5-6 months and 18-30 kg of body weight) were randomly assigned to five groups (n = 6) as follows: healthy control (HC), castration control (CAST), castration+carprofen (CAST+CRP), castration+xylazine (CAST+XYL), and castration+xylazine+carprofen (CAST+XYL+CRP). Plasma concentrations of carprofen were analyzed via a non-compartmental method. Physiological parameters including serum cortisol, scrotal temperature, rectal temperature, and scrotal circumference were determined. Xylazine caused a decrease in the volume of distribution and clearance and an increase in the area under the curve of carprofen in CAST+XYL+CRP group (p < 0.05). The mean cortisol concentrations in CAST+CRP and CAST+XYL remained lower compared to CAST (p < 0.05). The mean cortisol concentrations in CAST+XYL+CRP were lower than in CAST+CRP and CAST+XYL (p < 0.05). In addition, the effect of carprofen administration alone on reducing the initial cortisol response to castration was observed from 6 to 48 h, while in combination with xylazine, it was observed immediately up to 48 h. No treatment differences were observed in rectal temperature, scrotal temperature, and scrotal circumference (p > 0.05). Xylazine caused an increase in plasma concentration and a decrease in clearance of carprofen after co-administration. However, when the effect of the combined administration of carprofen with xylazine on cortisol is evaluated, their combined use in castration process may be beneficial.

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.

Effects of Temperature on the Pharmacokinetics, Tissue Residues, and Withdrawal Times of Doxycycline in Rainbow Trout (Oncorhynchus mykiss) following Oral Administration.

The purpose of this study was to compare the pharmacokinetics, tissue residues, and withdrawal times of doxycycline after oral administration in rainbow trout reared at 10 and 17 °C. Fish received a 20 mg/kg oral dose of doxycycline after a single or 5-day administration. Six rainbow trout were used at each sampling time point for plasma and tissue samples, including liver, kidney, and muscle and skin. The doxycycline concentration in the samples was determined using high-performance liquid chromatography with ultraviolet detector. The pharmacokinetic data were evaluated by non-compartmental kinetic analysis. The WT 1.4 software program was used to estimate the withdrawal times. The increase of temperature from 10 to 17 °C shortened the elimination half-life from 41.72 to 28.87 h, increased the area under the concentration-time curve from 173.23 to 240.96 h * µg/mL, and increased the peak plasma concentration from 3.48 to 5.50 µg/mL. At 10 and 17 °C, the doxycycline concentration was obtained in liver > kidney > plasma > muscle and skin. According to the MRL values stated for muscle and skin in Europe and China (100 µg/kg) and in Japan (50 µg/kg), the withdrawal times of doxycycline at 10 and 17 °C were 35 and 31 days, respectively, for Europe and China and 43 and 35 days, respectively, for Japan. Since temperature significantly affected pharmacokinetic behavior and withdrawal times of doxycycline in rainbow trout, temperature-dependent dosing regimens and withdrawal times of doxycycline might be necessary.

Vitamins E and A increase the passing of the P-gp substrate ivermectin into the brain in mice.

This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8-10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A.

Pharmacokinetics and pharmacokinetic interactions of orally administered oxfendazole and oxyclozanide tablet formulation to sheep.

The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three-period, crossover pharmacokinetic design and on six healthy Awassi sheep 1-3 years of age. The plasma concentrations of oxfendazole and its metabolites (fenbendazole and fenbendazole sulphone) and oxyclozanide were determined by high-performance liquid chromatography using an ultraviolet detector. Compounds recovered in plasma when oxfendazole was administered alone or combined with oxyclozanide were oxfendazole, fenbendazole sulphone, and fenbendazole, respectively. When oxfendazole was administered alone and co-administered with oxyclozanide, the AUCFBZ /AUCOFZ was 0.26 and 0.23, respectively, and the AUCFBZSO2 /AUCOFZ was 0.35 and 0.32, respectively. The volume of distribution (Vz/F) of oxfendazole was large in both groups. Oxyclozanide did not change the plasma disposition of oxfendazole. When the oxyclozanide tablet formulation was administered alone, the elimination half-life (21.35 h) and the Vz/F (940.17 ml/kg) were long and large, respectively. The area under the curve (AUC) and the maximum plasma concentration of oxyclozanide were significantly larger and higher, respectively, in the oxyclozanide plus oxfendazole group (1146.61 h × µg/ml and 29.80 µg/ml) compared with the oxyclozanide group (491.44 h × µg/ml and 14.24 µg/ml) while a significant decrease in apparent Vz/F (940.17 vs 379.14 ml/kg) and total clearance (30.52 vs 13.08 ml/h/kg) was detected. In conclusion, co-administration with oxfendazole causing an increase in the plasma profile of oxyclozanide may increase the antiparasitic activity of oxyclozanide.

The Usefulness of Serum Brain Damage Biomarkers in Detection and Evaluation of Hypoxic Ischemic Encephalopathy in Calves with Perinatal Asphyxia.

The purpose of the present study was to determine hypoxic brain damage in calves with perinatal asphyxia using brain-specific damage biomarkers. Ten healthy and 25 calves with perinatal asphyxia were enrolled in the study. Clinical examination, neurological status score, and laboratory analysis were performed at admission, 24, 48, and 72 h. Serum concentrations of ubiquitin carboxy-terminal hydrolysis 1 (UCHL1), calcium-binding protein B (S100B), adrenomodullin (ADM), activitin A (ACTA), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and creatine kinase-brain (CK-B) were measured. Histopathological and immunohistochemical examinations of the brain tissue were performed in 13 nonsurvivor calves. The neurological status score of the calves with asphyxia was significantly (p < 0.05) lower. Mix metabolic-respiratory acidosis and hypoxemia were detected in calves with asphyxia. Serum UCHL1 and S100B were significantly (p < 0.05) increased, and NSE, ACTA, ADM, and CK-B were decreased (p < 0.05) in calves with asphyxia. Histopathological and immunohistochemical examinations confirmed the development of mild to severe hypoxic-ischemic encephalopathy. In conclusion, asphyxia and hypoxemia caused hypoxic-ischemic encephalopathy in perinatal calves. UCHL1 and S100B concentrations were found to be useful markers for the determination of hypoxic-ischemic encephalopathy in calves with perinatal asphyxia. Neurological status scores and some blood gas parameters were helpful in mortality prediction.

Plasma and muscle tissue disposition of enrofloxacin in Nile tilapia (Oreochromis niloticus) after intravascular, intraperitoneal, and oral administrations.

The aim of the study was to investigate the plasma and muscle pharmacokinetic of enrofloxacin (ENR) and its active metabolite ciprofloxacin (CIP) in Nile tilapia (Oreochromis niloticus) following single intravascular (IV), intraperitoneal (IP), or oral (PO) administration at 30 ± 1 °C. In this study, 234 healthy Nile tilapia (120-150 g) were used. The fish received a single IV, IP, or PO treatment of ENR at a dose of 10 mg/kg. The plasma and muscle tissue concentrations of ENR and CIP were measured using high-performance liquid chromatography with fluorescence detection and were evaluated using non-compartmental analysis. The elimination half-life, volume of distribution at steady state, and total body clearance of ENR were 21.7 h, 2.69 L/kg, and 0.09 L/h/kg, respectively. The peak plasma concentrations of ENR after IP or PO administration were 6.11 and 4.21 µg/mL at 0.25 and 2 h, respectively. The bioavailability of ENR for IP or PO routes was 78% and 86%, respectively. AUC(0-120)muscle/AUC(0-120)plasma ratios following the IV, IP, or PO administrations were 1.43, 1.49, and 1.07, respectively. CIP was detected after all routes, but the AUC0-last ratios of CIP to ENR were <1.0% for plasma and muscle. ENR was detected up to 120 h following the IV, IP, or PO administrations. The long residence time of ENR after single IV, IP, or PO administration ensured the plasma concentration was ≥1 × MIC for bacteria with threshold MIC values of 0.92, 0.72, and 0.80 µg/mL over the whole 120 h observed. However, further studies are necessary to determine the optimum pharmacokinetic/pharmacodynamics data of ENR for the treatment of infections caused by susceptible bacteria in tilapia.

Pharmacokinetics of cefquinome in rainbow trout (Oncorhynchus mykiss) after intravascular, intraperitoneal, and oral administrations.

This study aimed to determine the pharmacokinetics and bioavailability of cefquinome in rainbow trout (Oncorhynchus mykiss) following intravascular (IV), intraperitoneal (IP), and oral (PO) administrations at 14 ± 1°C. In this study, three hundred and six clinically healthy rainbow trout (110-140 g) were used. The fish received single IV, IP, and PO injections of cefquinome at 10 mg/kg dose. The plasma concentrations of cefquinome were measured using HPLC-UV and were evaluated using non-compartmental analysis. Cefquinome was measured up to 96 h for PO route and 144 h for IV and IP routes in plasma. Following IV administration, t1/2ʎz , ClT , and Vdss were 18.85 h, 0.037 L/h/kg, and 0.84 L/kg, respectively. The Cmax of IP and PO routes was 9.75 and 1.64 µg/ml, respectively. The bioavailability following IP and PO administrations was 59.46% and 12.33%, respectively. Cefquinome at 10 mg/kg dose may maintain T > MIC above 40% at 72 and 96 h intervals, respectively, following the IP and IV routes for bacteria with MIC values of ≤2 µg/ml and at 24 h intervals following the PO route for bacteria with MIC value of ≤0.75 µg/ml. However, further studies are needed to determine in vitro and in vivo antibacterial efficacy and multiple dosage regimens of cefquinome against pathogens isolated from rainbow trout.

Pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) following intravenous, intramuscular, subcutaneous, and oral administrations.

The aim of this study was to determine the pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) after intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at 10 mg/kg dose. In this study, eight clinically healthy swan geese were used. The study was performed in four periods according to a crossover design with a 15 days washout period between two administrations. The plasma concentrations of danofloxacin were analyzed using high-performance liquid chromatograph-ultraviolet detection, and pharmacokinetic parameters were estimated by non-compartmental analysis. Following IV administration, terminal elimination half-life (t1/2ʎz ), total clearance, and volume of distribution at steady state were 6.03 h, 0.34 L/h/kg, and 2.71 L/h/kg, respectively. After IM, SC, and PO administration, t1/2ʎz was longer than that after IV administration. The Cmax of danofloxacin following IM, SC, and PO administrations was 3.65, 2.76, and 1.98 µg/mL at 0.63, 1, and 2 h, respectively. The bioavailability following IM, SC, and PO administrations was 87.99, 72.77, and 57.68%, respectively. This information may help in the use of danofloxacin in geese, yet the determination of optimal dosage regimen and pharmacodynamic studies are needed.

Pharmacokinetics of carprofen following single and repeated intravenous administrations of different doses in sheep.

The aim of this study was to determine the pharmacokinetics of carprofen following single and repeated intravenous (IV) administrations at 1.4 and 4 mg/kg doses in sheep. The study was carried out on twelve sheep in two experiments as single- and multiple-dose pharmacokinetics. In experiment 1, carprofen was administered via IV at single doses of 1.4 (n = 6) and 4 mg/kg (n = 6) in a randomized parallel design. In experiment 2, the same dose groups in experiment 1 following the 21-day washout period received intravenously carprofen every 24 h for 5 days. Plasma concentrations were measured using high-performance liquid chromatography-UV and analyzed by a two-compartment open model. After the single administration of 1.4 mg/kg dose, the t1/2α , t1/2el , MRT, ClT , Vdss , and AUC were 0.62 h, 27.57 h, 38.78 h, 2.72 ml/h/kg, 105.26 ml/kg, and 515.12 h*µg/ml, respectively. Carprofen at a single dose of 4 mg/kg showed prolonged t1/2el and MRT, and increased Vdss . On day 5 after the repeated administration of the 1.4 mg/kg dose, the t1/2α , t1/2el , MRT, ClT , Vdss , and AUC were 1.12 h, 57.48 h, 82.18 h, 0.55 ml/h/kg, 45.43 ml/kg, and 2532 h*µg/ml, respectively. Carprofen at a repeated dose of 4 mg/kg showed increased ClT and Vdss and decreased AUC/dose. Although the long t1/2ʎz in single and multiple IV dose studies suggest the possibility of its effective use, the IV route may not be practical in sheep. Therefore, oral and subcutaneous routes of carprofen in sheep would be more valuable in clinical settings.

Pharmacokinetics and bioavailability of carprofen in sheep.

The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations of a parenteral formulation at a dose of 4 mg/kg. A total of eight sheep were used for the investigation. The study comprised four periods, according to a crossover design with a 21-day washout period between treatments. Plasma concentrations of carprofen were measured using HPLC-UV. Pharmacokinetic parameters were estimated by non-compartmental model analysis. Following IV administration, t1/2ʎz , ClT , and Vdss were 43.36 h, 1.98 ml/h/kg, and 121.36 ml/kg, respectively. The Cmax(obs) was 26.57 mg/ml for the IM, 23.76 mg/ml for the SC, and 15.90 mg/ml for the PO. The bioavailability following IM, SC, and PO administrations was 75.47%, 82.00%, and 62.51%, respectively. Plasma creatine kinase activity increased significantly at 3, 6, and 12 h following IM administration of carprofen. Despite differences in plasma concentrations and bioavailability among administration routes, carprofen at 4 mg/kg dose may provide the plasma concentration (>1.5 µg/ml) needed for analgesic effect during 144 h in all routes. However, because of the slow absorption rate after SC and PO routes, the IV route may be preferred primarily for the rapid onset in the analgesic and anti-inflammatory effect of carprofen in sheep. Despite the favorable kinetics, the muscle damage caused by IM injection limits use of carprofen via IM route.

Can diarrhea affect the pharmacokinetics of racecadotril in neonatal calves?

This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t1/2ʎz , Cmax , Tmax, and AUC0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.