Metronidazole pharmacokinetics during rapid growth in turkeys – relation to changes in haemodynamics and drug metabolism

Whereas interspecies variation in pharmacokinetics is a commonly investigated issue, variations in drug kinetics within a species are less documented. The aim of the study was to assess the influence of age‐related changes in haemodynamics on the pharmacokinetics of metronidazole (MTZ) and its hydroxy metabolite (MTZ‐OH) in turkeys. MTZ was administered intravenously and orally at a dose of 25 mg/kg. Plasma drug and metabolite concentrations were assessed by high‐performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental analysis. Haemodynamic parameters (heart rate, stroke volume, cardiac output) were assessed by echocardiography and extraction ratio for MTZ was calculated based on total body clearance (Cl_B). Between the 5th and 15th week of age, Cl_B of MTZ decreased from 3.6 to 1.2 mL/min/kg causing a twofold increase in the mean residence time (MRT) and elimination half‐life (T_1/2el). The MTZ‐OH production decreased threefold and its MRT and T_1/2el increased. Although heart rate significantly decreased with age, cardiac output increased. Extraction ratio was low in all age groups. It is concluded that significant age‐dependent decrease in Cl_B of MTZ in turkeys resulted from decreased perfusion of the clearing organs and their reduced metabolic capacity. This phenomenon is probably species specific and may apply to other therapeutic agents.     

Pharmacokinetics of chloramphenicol following administration of intravenous and subcutaneous chloramphenicol sodium succinate,and subcutaneous chloramphenicol,to koalas (Phascolarctos cinereus)

Clinically normal koalas (n = 19) received a single dose of intravenous (i.v.) chloramphenicol sodium succinate (SS) (25 mg/kg; n = 6), subcutaneous (s.c.) chloramphenicol SS (60 mg/kg; n = 7) or s.c. chloramphenicol base (60 mg/kg; n = 6). Serial plasma samples were collected over 24–48 h, and chloramphenicol concentrations were determined using a validated high‐performance liquid chromatography assay. The median (range) apparent clearance (CL/F) and elimination half‐life (t_1/2) of chloramphenicol after i.v. chloramphenicol SS administration were 0.52 (0.35–0.99) L/h/kg and 1.13 (0.76–1.40) h, respectively. Although the area under the concentration–time curve was comparable for the two s.c. formulations, the absorption rate‐limited disposition of chloramphenicol base resulted in a lower median C_max (2.52; range 0.75–6.80 μg/mL) and longer median t_max (8.00; range 4.00–12.00 h) than chloramphenicol SS (C_max 20.37, range 13.88–25.15 μg/mL; t_max 1.25, range 1.00–2.00 h). When these results were compared with susceptibility data for human Chlamydia isolates, the expected efficacy of the current chloramphenicol dosing regimen used in koalas to treat chlamydiosis remains uncertain and at odds with clinical observations.     

The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits

The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)‐induced acute phase response (APR) on the pharmaco‐kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol‐amine (FFC‐a) were extracted from the plasma, and their concentrations were determined by high‐performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t‐test. The mean values of AUC_0–∞ in the endotoxaemic rabbits (26.3 ± 2.7 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 ± 0.97 μg·h/mL). The total mean plasma clearance (CL_T) decreased from 1228 ± 107.5 mL·h/kg in the control group to 806.4 ± 91.4 mL·h/kg in the LPS‐treated rabbits. A significant increase (P < 0.05) in the half‐life of elimination was observed in the endotoxaemic rabbits (5.59 ± 1.14 h) compared to the values observed in healthy animals (3.44 ± 0.57 h). In conclusion, the administration of repeated doses of 1 μg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half‐life and mean residence time (MRT), but a significant decrease in CL_T of the drug. As a consequence of the APR induced by LPS, there was a reduction in the metabolic conversion of FFC to their metabolite FFC‐a in the liver, suggesting that the mediators released during the APR induced significant inhibitory effects on the hepatic drug‐metabolizing enzymes.     

Effects of different dl‐selenomethionine and sodium selenite levels on growth performance,immune functions and serum thyroid hormones concentrations in broilers

This trial was conducted in a 2 × 3 + 1 factorial arrangement based on a completely randomized design to evaluate the effects of different dl ‐selenomethionine (dl ‐Se‐Met) and sodium selenite (SS) levels on growth performance, immune functions and serum thyroid hormones concentrations in broilers. A total of 840 Ross 308 broilers (7 days old) were allocated by body weight to seven treatments (three replicates of 40 birds each treatment) including (1) basal diet (containing 0.04 mg of selenium (Se)/kg; control) without supplementary Se; (2, 3 and 4) basal diet + 0.05, 0.15 or 0.25 mg/kg Se as SS; (5, 6 and 7) basal diet + 0.05, 0.15 or 0.25 mg/kg Se as dl ‐Se‐Met. The experiment lasted 42 days. The results revealed that dietary Se supplementation improved (p < 0.05) average daily gain, feed efficiency, immune organ index, serum immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM) and triiodothyronine (T₃) concentrations and decreased (p < 0.01) thyroxine (T₄)/T₃ ratio in serum compared with the control. Broilers receiving the dl ‐Se‐Met‐supplemented diets had higher (p < 0.05) feed efficiency, thymus index, the amounts of IgA, IgG, IgM and T₃ as well as lower (p < 0.05) serum T₄ concentrations and T₄/T₃ ratio than those consuming the SS‐supplemented diets. Serum IgA and IgM levels of broilers fed 0.15 mg Se/kg were significantly higher (p < 0.05) than those of broilers fed 0.05 or 0.25 mg Se/kg. In summary, we concluded that dl ‐Se‐Met is more effective than SS in increasing immunity and promoting conversion of T₄ to T₃, thus providing an effective way to improve the growth performance of broilers. Besides, based on a consideration of all experiment indices, 0.15 mg Se/kg was suggested to be the optimal level of Se supplementation under the conditions of this study.     

Pharmacokinetics and bioavailability of flumequine in blunt snout bream (Megalobrama amblycephala) after intravascular and oral administrations

In this study, the pharmacokinetic profile of flumequine (FMQ) was investigated in blunt snout bream (Megalobrama amblycephala) after intravascular (3 mg/kg body weight (b.w.)) and oral (50 mg/kg b.w.) administrations. The plasma samples were determinedby ultra‐performance liquid chromatography (UPLC) with fluorescence detection. After intravascular administration, plasma concentration–time curves were best described by a two‐compartment open model. The distribution half‐life (t_1/2α), elimination half‐life (t_1/2β), and area under the concentration–time curve (AUC) of blunt snout bream were 0.6 h, 25.0 h, and 10612.7 h·μg/L, respectively. After oral administration, a two‐compartment open model with first‐order absorption was also best fit the data of plasma. The t_1/2α, t_1/2β, peak concentration (C_max), time‐to‐peak concentration (T_max), and AUC of blunt snout bream were estimated to be 2.5 h, 19.7 h, 3946.5 μg/L, 1.4 h, and 56618.1 h. μg/L, respectively. The oral bioavailability (F) was 32.0%. The pharmacokinetics of FMQ in blunt snout bream displayed low bioavailability, rapid absorption, and rapid elimination.     

Pharmacokinetic indices for cefovecin after single‐dose administration to adult sea otters (Enhydra lutris)

Seven sea otters received a single subcutaneous dose of cefovecin at 8 mg/kg body weight. Plasma samples were collected at predetermined time points and assayed for total cefovecin concentrations using ultra‐performance liquid chromatography and tandem mass spectrometry. The mean (±SD) noncompartmental pharmacokinetic indices were as follows: C_Max (obs) 70.6 ± 14.6 μg/mL, T_{Max (obs)} 2.9 ± 1.5 h, elimination rate constant (k_el) 0.017 ± 0.002/h, elimination half‐life (t_1/2kel) 41.6 ± 4.7 h, area under the plasma concentration‐vs.‐time curve to last sample (AUC_last) 3438.7 ± 437.7 h·μg/mL and AUC extrapolated to infinity (AUC_0→∞) 3447.8 ± 439.0 h·μg/mL. The minimum inhibitory concentrations (MIC) for select isolates were determined and used to suggest possible dosing intervals of 10 days, 5 days, and 2.5 days for gram‐positive, gram‐negative, and Vibrio parahaemolyticus bacterial species, respectively. This study found a single subcutaneous dose of cefovecin sodium in sea otters to be clinically safe and a viable option for long‐acting antimicrobial therapy.     

Comparative pharmacokinetics of acetylsalicylic acid and sodium salicylate in chickens and turkeys

1. Pharmacokinetics of acetylsalicylic acid (ASA) and sodium salicylate (SS) were assessed following single intravenous (i.v.) and oral administration at doses of 50 mg/kg body weight to chickens and turkeys. Plasma drug concentrations were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model.

2. The mean residence time (MRT) of salicylate (SA) after i.v. administration of SS was 6.08 ± 0.59 and 3.32 ± 0.27 h and after oral administration was 6.95 ± 0.72 and 4.55 ± 0.71 h in chickens and turkeys, respectively. The elimination half-life (T _{1/2 e}) was shorter in turkeys compared with chickens. The value of body clearance (Cl_B) was higher in turkeys than in chickens, but the apparent volume of distribution (V _ss) was similarly low in both species. The bioavailability of SS was complete and the maximal plasma concentration of SA (C _max) after oral administration was 96.93 ± 8.06 and 91.76 ± 9.64 µg/ml, respectively, in chickens and turkeys.

3. The MRT of ASA after iv administration was 0.24 ± 0.08 and 0.24 ± 0.02 h and after oral administration was 0.78 ± 0.25 and 0.59 ± 0.13 h, respectively, in chickens and turkeys. In both species, T _{1/2 e} was very short, Cl_B and V _ss were similar and markedly higher than those of salicylate. The bioavailability of unchanged ASA was low and C _max after oral administration was 6.9 ± 3.6 µg/ml in chickens and 8.6 ± 1.3 µg/ml in turkeys.     

Pharmacokinetics of florfenicol after intravenous administration in Escherichia coli lipopolysaccharide‐induced endotoxaemic sheep

Experiments in different animal species have shown that febrile conditions, induced by Escherichia coli lipopolysaccharide (LPS), may alter the pharmacokinetic properties of drugs. The objective was to study the effects of a LPS‐induced acute‐phase response (APR) model on plasma pharmacokinetics of florfenicol (FFC) after its intravenous administration in sheep. Six adult clinically healthy Suffolk Down sheep, 8 months old and 35.5 ± 2.2 kg in body weight (bw), were distributed through a crossover factorial 2 × 2 design, with 4 weeks of washout. Pairs of sheep similar in body weight were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS before FFC treatment. Group 2 (control) was treated with an equivalent volume of saline solution (SS) at similar intervals as LPS. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples (5 mL) were collected before drug administration and at different times between 0.05 and 48.0 h after treatment. FFC plasma concentrations were determined by liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using a Mann–Whitney U‐test. The mean values of AUC_0–∞ in the endotoxaemic sheep (105.9 ± 14.3 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy sheep (78.4 ± 5.2 μg·h/mL). The total mean plasma clearance (CL_T) decreased from 257.7 ± 16.9 mL·h/kg in the control group to 198.2 ± 24.1 mL·h/kg in LPS‐treated sheep. A significant increase (P < 0.05) in the terminal half‐life was observed in the endotoxaemic sheep (16.9 ± 3.8 h) compared to the values observed in healthy sheep (10.4 ± 3.2 h). In conclusion, the APR induced by the intravenous administration of E. coli LPS in sheep produces higher plasma concentrations of FFC due to a decrease in the total body clearance of the drug.     

Pharmacokinetics of enrofloxacin in snakehead fish,Channa argus

The pharmacokinetics of enrofloxacin (EF) was investigated after single intravenous (i.v.) and oral (p.o.) dose of 10 mg/kg body weight (b.w.) in snakehead fish at 24–26 °C. The plasma concentrations of EF and its metabolite ciprofloxacin (CF) were determined by high‐performance liquid chromatography. The plasma concentration–time data were described by an open two‐compartment model for both routes. After intravenous administration, the elimination half‐life (T_1/2β), area under the concentration–time curve (AUC) and total body clearance of EF were 19.82 h, 75.79 μg h/mL and 0.13 L/h/kg, respectively. Following p.o. administration, the maximum plasma concentration (C_max), T_1/2β and AUC of EF were 1.86 μg/mL, 35.8 h and 49.98 μg h/mL, respectively. Absorption of EF was good with a bioavailability (F) of 65.82%, which was higher than that calculated in most seawater fish. CF, an active metabolite of EF, was detected occasionally in this study, which indicates a low extent of deethylation of EF in snakehead fish.     

Pharmacokinetics of florfenicol in blunt‐snout bream (Megalobrama amblycephala) at two water temperatures with single‐dose oral administration

The pharmacokinetics and residue elimination of florfenicol (FFC) and its metabolite florfenicol amine (FFA) were studied in healthy blunt‐snout bream (Megalobrama amblycephala, 50 ± 10 g). The study was conducted with a single‐dose (25 mg/kg) oral administration at a water temperature of 18 or 28°C, while in the residue elimination study, fish were administered at 25 mg/kg daily for three consecutive days by oral gavage to determine the withdrawal period (WDT) at 28°C. The FFC and FFA levels in plasma and tissues (liver, kidneys and muscle) were analysed using high‐performance liquid chromatography (HPLC). A no‐compartment model was used to analyse the concentration versus time data of M. amblycephala. In the two groups at 18 and 28°C, the maximum plasma concentration (C_max) of FFC was 5.89 and 6.21 μg/ml, while the time to reach C_max (T_max) was 5.97 and 2.84 hr, respectively. These suggested that higher temperature absorbed more drug and more quickly at M. amblycephala. And the elimination half‐life (T_1/2kβ) of FFC was calculated as 26.75 and 16.14 hr, while the total body clearance (CL) was 0.09 and 0.15 L kg^?1 hr^?1, and the areas under the concentration–time curves (AUCs) were 265.87 and 163.31 μg hr/ml, respectively. The difference demonstrated that the elimination rate of FFC in M. amblycephala at 28°C was more quickly than that at 18°C. The results of FFA showed the same trend in tissues of M. amblycephala. After multiple oral doses (25 mg/kg daily for 3 days), the k (eliminate rate constant) of FFA in M. amblycephala muscle was 0.017, the C₀ (initial concentration) was 3.07 mg/kg, and the WDT was 10 days (water temperature 28°C).     

Comparative pharmacokinetics of norfloxacin nicotinate in common carp (Cyprinus carpio) and crucian carp (Carassius auratus) after oral administration

Comparative pharmacokinetics of norfloxacin nicotinate (NFXNT) was investigated in common carp (Cyprinus carpio) and crucian carp (Carassius auratus) after a single oral dose of 10 mg/kg body weight (b.w.). Analyses of plasma samples were performed using ultra‐performance liquid chromatography (UPLC) with fluorescence detection. After oral dose, plasma concentration–time curves of common carp and crucian carp were best described by a two‐compartment open model with first‐order absorption. The pharmacokinetic parameters of common carp were similar to those of crucian carp. The distribution half‐life (t_1/2α), elimination half‐life (t_1/2β), peak concentration (C_max), time‐to‐peak concentration (T_max), and area under the concentration–time curve (AUC) of common carp were 1.58 h, 26.33 h, 6069.79 μg/L, 1.08 h, and 103072.36 h·μg/L, respectively, and those corresponding to crucian carp were 1.36 h, 26.55 h, 9586.06 μg/L, 0.84 h, and 126604.4 h·μg/L, respectively. These studies demonstrated that 10 mg NFXNT/kg body weight in common carp and crucian carp following oral dose presented good pharmacokinetic characteristics.     

Effects of calcium soap of rice bran oil fatty acids supplementation alone and with DL‐α‐tocopherol acetate in lamb diets on performance,digestibility, ruminal parameters and meat quality

Thirty‐six Malpura lambs (28 day old and 6.7 ± 0.25 kg BW) were distributed equally in three groups having six males and six female. They were ad libitum fed individually three different experimental diets containing calcium soap of fatty acids (CA‐FA) at 0 (T₁) and 40 (T₂ and T₃) g/kg concentrate up to six months of age. Animals in T₃ were supplemented additionally with 40 mg DL‐α‐tocopherol acetate/kg of concentrate. The roughage moiety included ad libitum dry Prosopis cineraria and fresh Azadirachata indica leaves. All the lambs were allowed to suckle from their dam up to weaning (90 day of age). Supplementation of Ca‐FA improved weight gain and feed conversion ratio during both pre‐ (28–90 days) and post‐weaning (91–180 days) phases; however, no effect of DL‐α‐tocopherol was observed. Metabolic parameters during post‐weaning phase revealed non‐significant effect on digestibility but improved nitrogen balance in the test groups. The effect on biochemical attributes did not show any significant alteration in ruminal parameters, blood biochemicals and urinary purine derivatives. Carcass traits revealed higher (p < 0.05) dressing yield and loin eye area with Ca‐FA supplementation. The value of thiobarbituric reactive substances for nuggets prepared from frozen carcasses revealed significant (p < 0.05) reduction in T₃ compared to the other dietary groups. Fatty acid profile of adipose tissue revealed higher (p < 0.001) 9‐octadecanoic, 9‐12‐octadecadienoic, polyunsaturated fatty acids (PUFA), higher ratio of PUFA/saturated fatty acids (SFA), ω‐6/ω‐3 and lower SFA in Ca‐FA‐supplemented groups. It is concluded that supplementation of 40 g/kg calcium soap prepared from industrial grade rice bran oil in lamb ration provided additional energy intake, improved N utilization, gain and feed conversion ratio besides improving dressing yield and meat quality with CLA enriched fatty acid profile. DL‐α‐tocopherol acetate when supplemented at 40 mg/kg feed reduced lipid oxidation of meat products thus improving its keeping quality.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Plasma disposition kinetics of moxidectin after subcutaneous administration to pregnant sheep

The plasma kinetic profile of moxidectin (MXD) in ewes during the last third of pregnancy was studied after the subcutaneous dose of 0.2 mg/kg of body weight (bw). Two groups of sheep (n = 7) that were equally balanced in body weight were used. Group I (control) was maintained unmated, while Group II (pregnant) was estrous‐synchronized and mated with fertile rams. Both groups were maintained under similar conditions regarding management and feeding. When the ewes from Group II fulfilled 120 days of pregnancy, both groups were treated with a subcutaneous injection of 0.2 mg of MXD/kg bw. Blood samples were collected at different set times between 1 h and 40 days post‐treatment. After plasma extraction and derivatization, the samples were analyzed using high‐performance liquid chromatography with fluorescence detection. A noncompartmental pharmacokinetic analysis was performed, and the data were compared using Student's t‐test. The mean pharmacokinetic parameters, including C_max, T_max, and the area under the concentration–time curve (AUC), were similar for both groups of sheep. The average of elimination half‐life was significantly lower (P = 0.0023) in the pregnant (11.49 ± 2.2 days) vs. the control (17.89 ± 4.84 days) sheep. Similarly, the mean residence time (MRT) for the pregnant group (20.6 ± 3.8 days) was lower (P = 0.037) than that observed in the control group (27.4 ± 9.1 days). It is concluded that pregnancy produces a significant decrease in mean values of half‐life of elimination of MXD, indicating that pregnancy can increase the rate of elimination of the drug reducing their permanence in the body.     

Plasma pharmacokinetics and muscle residue dynamics of mebendazole in Carassius auratus

Mebendazole is approved for use in aquatic animals and is widely used in Chinese aquaculture. We developed a pharmacokinetic and residue analysis for mebendazole levels in the goldfish (Carassius auratus). Plasma and muscle samples of C. auratus were taken after oral administration of 10 mg/kg mebendazole. The maximal drug plasma concentration of 0.55 mg/L was achieved at 48 hr and then declined with the elimination half‐life (T_1/2β) of 7.99 hr. Administration of 10 mg/kg by oral gavage for 5 successive days resulted in a peak mebendazole concentration of 0.70 mg/kg in muscle at 96 hr after the last dose. The drug was then eliminated at a relatively slow rate from muscle with T_1/2β of 68.41 hr. There was no detectable mebendazole in any muscle samples at 24 days postadministration. The AUC_last in plasma and muscle was 19.42 and 105.33 mg hr/L, respectively. These data provide information for dosage recommendations and withdrawal time determinations for mebendazole use in aquariums.     

Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK‐PD modeling analysis in pigs

Florfenicol, a structural analog of thiamphenicol, has broad‐spectrum antibacterial activity against gram‐negative and gram‐positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic–pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E. coli) with PK‐PD integrated model in the target infectious tissue. 220 E. coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC₅₀ (8 μg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time‐killing curves also coincided with the MBC determination. The recommended dosages (30 mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC_24 hr, AUC_0–∞, T_max, T_1/2, C_max, CL_b, and K_e were 49.83, 52.33 μg*h/ml, 1.32, 10.58 hr, 9.12 μg/ml, 0.50 L/hr*kg, 0.24 hr^?1 and 134.45, 138.71 μg*hr/ml, 2.05, 13.01 hr, 16.57 μg/ml, 0.18 L/hr*kg, 0.14 hr^?1 in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52 mg/kg for 50% target and 33.95, 39.79, and 42.55 mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16 μg/ml. The current data presented provide the optimal regimens (39.79 mg/kg) and susceptible breakpoint (16 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.     

Pharmacokinetic profile of Ceftiofur Hydrochloride Injection in lactating Holstein dairy cows

Ceftiofur (CEF), a broad‐spectrum third‐generation cephalosporin, exhibits a good activity against a broad range of gram‐negative and gram‐positive bacteria, including many that produce β‐lactamase. To design a rational dosage regimen for the drug in lactating Holstein dairy cows, the pharmacokinetic properties of ceftiofur hydrochloride injection were investigated in six cows after intravenous, intramuscular, and subcutaneous administration of single dose of 2.2 mg/kg BW (body weight). Plasma concentration–time curves and relevant parameters were best described by noncompartmental analysis through WinNonlin 6.3 software. After subcutaneous administration, the absolute bioavailability was 61.12% and the T_1/2λz (elimination half‐life) was 8.67 ± 0.72 hr. The C_max (maximum plasma concentration) was 0.88 ± 0.21 μg/ml and T_max (the time after initial injection to when C_max occurs) was 1.50 ± 0.55 hr. The MRT (mean residence time) was 11.00 ± 0.30 hr. Following intramuscular administration, the C_max (1.09 ± 0.21 μg/ml) was achieved at T_max (1.20 ± 0.26 hr) with an absolute availability of 70.52%. In this study, the detailed pharmacokinetic profiles of free and total CEF showed that this drug is widely distributed and rapidly eliminated and may contribute to a better understanding of the usage of ceftiofur hydrochloride injection in Holstein dairy cows.     

Comparative pharmacokinetics of enrofloxacin in healthy and Aeromonas hydrophila‐infected crucian carp (Carassius auratus gibelio)

The comparative pharmacokinetics of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in healthy and Aeromonas hydrophila‐infected crucian carp after a single oral (p.o.) administration at a dose of 10 mg/kg at 25 °C. The plasma concentrations of ENR and of CIP were determined by HPLC. Pharmacokinetic parameters were calculated based on mean ENR concentrations by noncompartmental modeling. In healthy fish, the elimination half‐life (T_1/2λz), maximum plasma concentration (C_max), time to peak (T_max), and area under the concentration–time curve (AUC) values were 64.66 h, 3.55 μg/mL, 0.5 h, and 163.04 μg·h/mL, respectively. In infected carp, by contrast, the corresponding values were 73.70 h, 2.66 μg/mL, 0.75 h, and 137.43 μg·h/mL, and the absorption and elimination of ENR were slower following oral administration. Very low levels of CIP were detected, which indicates a low extent of deethylation of ENR in crucian carp.     

Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus)

Clinically normal koalas (n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady‐state volume of distribution (V_ss) were 0.31 (0.11–0.55) L/h/kg and 0.92 (0.38–1.40) L/kg, respectively. The elimination half‐life (t_1/2) was much shorter than in many species (i.v.: median 2.25, range 0.98–6.51 h; p.o.: 4.69, range 2.47–8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20–0.97). Absorption rate‐limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution (V_area) displayed an allometric relationship with other mammals, CL and t_1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t_1/2) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h.     

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

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