Population Pharmacokinetics of Danofloxacin in Yellow River Carp (Cyprinus carpio haematopterus) After One Single Oral Dose.

This study aimed to determine the population pharmacokinetics of danofloxacin in healthy Yellow River carp (Cyprinus carpio Haematopterus) after single oral administration at 10 mg/kg body weight (BW). A sparse sampling was applied in this study and plasma samples were randomly collected from the tail veins of six carp at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 and 144 h after administration. A maximum of four plasma samples was collected from each carp. Then the concentrations of danofloxacin in plasma samples were determined through an HPLC method. Danofloxacin could be quantified in plasma up to 144 h after administration. The corresponding population pharmacokinetic modeling was developed according to the non-linear mixed effect method, including covariate and covariance models to explain some variations from unknown sources and improve the prediction ability. On the premise of sparse sampling, the typical values of the population (fixed effect) and inter-individual variation (random effect) were described by the current population pharmacokinetic model. The estimated typical values and coefficient of variation between individuals (CV%) of absorption rate constant (tvKa), apparent distribution volume (tvV) and clearance (tvCL) were 2.48 h-1 and 0.203%, 47.8 L/kg and 8.40%, 0.694 L/h/kg and 4.35%, respectively. The current danofloxacin oral dosing (10 mg/kg BW) can provide suitable plasma concentrations to inhibit those pathogens with MIC values below 0.016 µg/ml based on the calculated PK/PD indices of AUC/MIC or Cmax/MIC. Further studies are still needed to determine the in vitro and in vivo antibacterial efficacy of danofloxacin against pathogens isolated from Yellow River carp and finally draw a reasonable dosing regimen.

Development and application of a physiologically based pharmacokinetic model for orbifloxacin in crucian carp (Carassius auratus).

A flow-limited physiologically based pharmacokinetic (PBPK) model consisting of seven compartments was established for orbifloxacin in crucian carp to predict drug concentrations after intravenous or intramuscular injections. Physiological and anatomical parameters, including tissue weights and blood flow through different tissues, were obtained from previous literature. The tissue/plasma partition coefficients for orbifloxacin were calculated using the area method or parameter optimization. In addition, their values were 0.9326, 1.1204, 1.1644, 1.3514, and 2.0057 in the liver, skin, muscle, kidney, and the rest of the body compartment, respectively. Based on the current PBPK model, orbifloxacin concentrations were predicted and compared with those previously reported for further validation. In addition, the mean absolute percentage error (MAPE) values were also calculated, with values ranging from 10.21% in plasma to 42.37% in kidneys, indicating acceptable predictions for all tissues and plasma. A local sensitivity analysis was performed, which showed that the parameters related to elimination and distribution were most influential on orbifloxacin concentrations in muscle. This model was finally used to predict plasma and tissue concentrations after multiple intramuscular dosing. The current PBPK model provided a valuable tool for predicting the tissue residues of orbifloxacin in crucian carp following intramuscular injection.

Pharmacokinetics and Tissue Distribution of Enrofloxacin Following Single Oral Administration in Yellow River Carp (Cyprinus carpio haematoperus).

The pharmacokinetics and tissue distribution of enrofloxacin were determined in Yellow River carp (Cyprinus carpio haematopterus) reared at 20°C after single oral administration of enrofloxacin at 10 mg·kg-1 body weight (BW). Plasma, bile, and different tissue samples, including liver, kidney, gill, gut, and skin-muscle, were collected at predetermined times points. An HPLC method was developed to simultaneously determine the concentrations of enrofloxacin and its metabolite, ciprofloxacin. However, ciprofloxacin was only detectable in some liver samples with trace levels. Then the average enrofloxacin concentrations vs. time data were subjected to a non-compartmental analysis using WinNonLin 5.2 software. Multiple peaking profiles were observed in all enrofloxacin concentration-time curves. The peak concentration (Cmax) values were observed as 0.79, 1.01, 2.09, 2.85, 4.34, 10.78, and 13.07 µg·ml-1 (or g-1) in plasma, skin-muscle, gill, kidney, liver, bile, and gut, respectively, and the corresponding time to reach peak concentration (Tmax) was 8, 8, 1, 8, 1, 72, and 4 h, respectively. The values of elimination half-life (T1/2λZ ) of enrofloxacin in different tissues was in the following order: gill (291.13 h) > liver (222.29 h) > kidney (157.22 h) > plasma (129.44 h) > gut (91.47 h) > skin-muscle (87.77 h) > bile (86.22 h). The present results showed that enrofloxacin had a wide distribution in different tissues, however slow absorption and elimination in Yellow River carp. Additionally, enrofloxacin exhibited large distribution in bile, indicating that bile excretion might be the primary elimination route of enrofloxacin in Yellow River carp. A withdrawal period was calculated as 379.2 °C-day for single oral dosing of enrofloxacin at 10 mg/kg BW. Based on the calculated PK/PD indices of AUC/MIC or Cmax/MIC, the current enrofloxacin dosing regimen might have a positive therapeutic effect on the infection of Flavobacterium columnare, Aeromonas sobria, or Aeromonas hydrophila. However, the depletion study following multiple oral doses should be carried out in Yellow River carp reared at lower temperatures, and the withdrawal period should also be further calculated.

Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection.

The present study aimed to determine the pharmacokinetic profiles of ceftiofur (as measured by ceftiofur and its active metabolites concentrations) in a small-size dog breed, Peekapoo, following a single intravenous or subcutaneous injection of ceftiofur sodium. The study population comprised of five clinically healthy Peekapoo dogs with an average body weight (BW) of 3.4 kg. Each dog received either intravenous or subcutaneous injection, both at 5 mg/kg BW (calculated as pure ceftiofur). Plasma samples were collected at different time points after the administration. Ceftiofur and its active metabolites were extracted from plasma samples, derivatized, and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetic parameters. The terminal half-life (t1/2 λz ) was calculated as 7.40 ± 0.79 and 7.91 ± 1.53 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (VSS ) were determined as 39.91 ± 4.04 ml hr-1  kg-1 and 345.71 ± 28.66 ml/kg, respectively. After subcutaneous injection, the peak concentration (Cmax ; 10.50 ± 0.22 µg/ml) was observed at 3.2 ± 1.1 hr, and the absorption half-life (t1/2 ka ) and absolute bioavailability (F) were calculated as 0.74 ± 0.23 hr and 91.70%±7.34%, respectively. The pharmacokinetic profiles of ceftiofur and its related metabolites demonstrated their quick and excellent absorption after subcutaneous administration, in addition to poor distribution and slow elimination in Peekapoo dogs. Based on the time of concentration above minimum inhibitory concentration (T > MIC) values calculated here, an intravenous or subcutaneous dose at 5 mg/kg of ceftiofur sodium once every 12 hr is predicted to be effective for treating canine bacteria with a MIC value of ≤4.0 µg/ml.

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

Enrofloxacin (ENR) has been approved for the treatment of infections in aquaculture, but it may cause tissue residue. This research aimed to develop and validate a water temperature related PBPK model, including both ENR and ciprofloxacin (CIP), in rainbow trout, and to predict further their residue concentrations and the withdrawal periods for ENR at different water temperatures. With the published concentrations data, a flow-limited PBPK model including both ENR and CIP sub-models was developed to predict ENR and CIP concentrations in tissues and plasma/serum after intravenous, oral, or immersion administration. A Monte Carlo simulation including 500 iterations was further incorporated into this model. Based on the model and Monte Carlo analysis, the withdrawal intervals were estimated for different dosage regimens and at different water temperatures, ranging from 80 to 272 degree-days. All of these values were shorter than the labeled withdrawal period (500 degree-days) in fish. This model provided a useful tool for predicting the tissue residues of ENR and CIP in rainbow trout under different dosage regimens and at different water temperatures.

Depletion study and withdrawal period calculation of florfenicol in the crucian carp (Carassius auratus) following multiple intramuscular injections.

The previously adopted marker residue for florfenicol (FF) in China was only florfenicol amine (FFA); however, the marker residue has been changed to FF plus FFA since the end of 2017. The previous official withdrawal period determined based on the only concentration of FFA may no longer be suitable. Therefore, the present study aimed to determine the depletion profiles of FF and FFA and further calculate the withdrawal period in the crucian carp (Carassius auratus) based on the new marker residues. Florfenicol was intramuscularly administered at 10 mg/kg bodyweight daily for five consecutive days to crucian carps reared in freshwater at 10°C. After the last dose, plasma and tissue samples were randomly collected from 10 fish at different time points. The FF and FFA concentrations were simultaneously determined by high-performance liquid chromatography (HPLC) with a fluorescence detector and further subjected to noncompartmental analysis. The elimination half-life (h) of FF in different tissues decreased as follows: liver (39.1) > kidney (36.3) > skin plus muscle (34.6) > plasma (31.7), whereas that of FFA decreased as follows: kidney (41.4) > skin plus muscle (39.4) > liver (39.3) > plasma (35.7). Considering a maximum residue limit of 1 µg/g for the total concentration of FF and FFA in the skin plus muscle, a withdrawal period of 6 days was calculated based on the upper limit of the one-sided 95% confidence interval.