Z. L. Zeng

Use of a Monte Carlo analysis within a physiologically based pharmacokinetic model to predict doxycycline residue withdrawal time in edible tissues in swine

The pharmacokinetics of doxycycline were studied following a single intravenous (I.V.) and intramuscular (I.M.) injection of 10u2009mg/kg into eight healthy pigs. The steady-state tissue/plasma partition coefficients were obtained via a 3-h constant rate infusion (CRI) in four pigs. Based on the results of in vivo studies and the parameters derived from published work, a physiologically based pharmacokinetic (PBPK) model was developed to predict the drug concentration in edible tissues. The predicted values were then compared with those derived from a previous study. To account for individual differences in the processes of drug metabolism and/or diffusion, a Monte Carlo (MC) run of 1000 simulations was incorporated into the PBPK model to predict the doxycycline residue withdrawal times in edible tissues in swine. The withdrawal periods were compared with those derived from linear regression analysis. The PBPK model presented here provided accurate predictions of the observed concentrations in all tissues except for the injection site. The withdrawal times in all edible tissues derived from the MC analysis were longer than those from linear regression analysis. Based on the residues in the injection site and muscle tissue, the MC analysis predicted a withdrawal time of 33 days. Here, we illustrate that MC analysis can be incorporated into the PBPK model to accurately predict doxycycline residue withdrawal time in edible tissues in swine.

Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Pasteurella multocida in a tissue-cage model in yellow cattle

The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1xa0mg/kg of body weight in a two-period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue-cage fluid (exudate), and noninflamed tissue-cage fluid (transudate) were studied using a tissue-cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P.xa0multocida) were determined. A concentration-independent antimicrobial activity of cefquinome was confirmed for levels lower than 4xa0×xa0MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (Txa0>xa0MIC) in serum was 14.10xa0h after intravenous and 14.46xa0h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P.xa0multocida of MIC 0.04xa0μg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.

A physiologically based pharmacokinetics model for florfenicol in crucian carp and oral‐to‐intramuscular extrapolation

In this study, an oral physiologically based pharmacokinetics (PBPK) model was developed for florfenicol in crucian carp (Carassius auratus). Subsequently, oral-to-intramuscular extrapolation was performed and the two models were used to predict florfenicol concentrations in the edible tissues of crucian carp. The oral model gave good predictions in most tissues, except for kidney and liver in which the florfenicol concentrations were underestimated at the later time points. In contrast, using the intramuscular model, the concentrations in the kidney were overestimated at the later time points. Both models had the best predictive ability in the main edible tissue, the muscle. The oral model also accurately predicted the florfenicol concentrations in the muscle after multiple doses. The present study demonstrated the feasibility of predicting florfenicol concentrations in the edible tissues of crucian carp using a route-to-route extrapolation method.

Pharmacokinetics of Mequindox and Its Metabolites in Swine

Abstract The present study was carried out to investigate the pharmacokinetics of mequindox (MEQ), a new synthetic quinoxaline 1,4-dioxide derivative and its two main metabolites M1 [2-isoethanol mequinoox], M2 [2-isoethanol 1-desoxymequindox] in healthy swine. MEQ (10 mg kg −1 body weight) was administered to nine healthy cross-bread swine via oral, intramuscular, and intravenous routes in a randomized 3×3 crossover design with a 1-wk washout period. A sensitive high-performance liquid chromatography (HPLC) method was used for the determination of plasma concentrations of MEQ and its metabolites M1 and M2. Plasma concentration versus time profiles of MEQ and its metabolites, M1 and M2, were analyzed by non-compartmental analysis using WinNonlin 5.2 software. The mean maximum concentrations (C max ) of M1 and M2 after intravenous administration of MEQ were (5.27±1.59) μg mL −1 at 1.78 h and (1.01±0.29) μg mL −1 at 0.92 h, respectively. The mean maximum concentrations (C max ) of MEQ, M1, and M2 were found to be (6.96±3.23), (6.61±1.56), and (0.78 ±0.25) μg mL −1 , respectively at 0.15, 1.61, and 1.30 h after intramuscular administration of MEQ, respectively and (0.75±0.45), (6.90±1.52), and (0.62±0.21) μg mL −1 , respectively at 0.40, 1.57, and 2.00 h, respectively after oral administration of MEQ. The apparent elimination half-lives (t 1/2 ) of MEQ, M1, and M2 were (0.84±0.35), (7.57±3.93), and (9.56±6.00) h, respectively after intravenous administration of MEQ; (0.50±0.25), (6.30±3.00), and (5.94±2.54) h, respectively after intramuscular administration of MEQ; and (1.64±1.17), (5.59±1.93), and (16.25±10.27) h, respectively after oral administration of MEQ. The mean areas under the plasma concentration-time curve (AUC 0- of MEQ, M1, and M2 were (4.88±1.54), (36.93±17.50), and (5.16±1.94) μg h mL- 1 , respectively after intravenous administration of MEQ; (4.18±0.76), (48.25±20.82), and (4.88±2.21) μg h mL −1 , respectively after intramuscular administration of MEQ; and (1.01±0.40), (48.83±20.71), and (5.54±2.23) μg h mL −1 , respectively after oral administration of MEQ. MEQ was rapidly absorbed and metabolized in swine after oral, intramuscular, and intravenous administration. Further studies are required to investigate the double-peak phenomenon observed in the plasma concentration-time profile after oral administration and the pharmacokinetics of other metabolites of MEQ.

Pharmacokinetics of doxycycline in tilapia (Oreochromis aureus × Oreochromis niloticus) after intravenous and oral administration

The pharmacokinetics of doxycycline was studied in plasma after a single dose (20 mg/kg) of intravenous or oral administration to tilapia (Oreochromis aureus × Oreochromis niloticus) reared in fresh water at 24 °C. Plasma samples were collected from six fish per sampling point. Doxycycline concentrations were determined by high-performance liquid chromatography with a 0.005 μg/mL limit of detection, then were subjected to noncompartmental analysis. Following oral administration, the double-peak phenomenon was observed, and the first (Cmax1 ) and second (Cmax2) peaks were 1.99 ± 0.43 μg/mL at 2.0 h and 2.27 ± 0.38 μg/mL at 24.0 h, respectively. After the intravenous injection, a Cmax2 (12.12 ± 1.97 μg/mL) was also observed, and initial concentration of 45.76 μg/mL, apparent elimination rate constant (λz) of 0.018 per h, apparent elimination half-life (t1/2λz) of 39.0 h, systemic total body clearance (Cl) of 41.28 mL/h/kg, volume of distribution (Vz) of 2323.21 mL/kg, and volume of distribution at steady-state (Vss) of 1356.69 mL/kg were determined, respectively. While after oral administration, the λz, t1/2λz, and bioavailability of doxycycline were 0.009 per h, 77.2 h, and 23.41%, respectively. It was shown that doxycycline was relatively slowly and incompletely absorbed, extensively distributed, and slowly eliminated in tilapia, in addition, doxycycline might undergo enterohepatic recycling in tilapia.

Estimating tulathromycin withdrawal time in pigs using a physiologically based pharmacokinetics model.

A physiologically based pharmacokinetics model was developed to predict tulathromycin concentrations in edible swine tissues. Physiological parameters included volumes of and plasma flows through different tissues which were obtained from the literatures. The tissue/plasma partition coefficient was calculated according to the area method, and the model was validated through a comparison of predicted and observed concentrations. Withdrawal times in different tissues were predicted. The physiologically based pharmacokinetics model presented here provided accurate predictions of the observed concentrations in all tissues. The results showed that the injection site had the longest withdrawal time (21 days), followed by skin together with fat (19 days) and then kidney (10 days), lung (6 days), liver (4 days) and muscle (1 day). A withdrawal time of 21 days was finally predicted for tulathromycin in swine after a single intramuscular injection at 2.5 mg/kg body weight.

Estimating danofloxacin withdrawal time in broiler chickens based on physiologically based pharmacokinetics modeling

In this study, a physiologically based pharmacokinetics (PBPK) model was firstly developed for danofloxacin in healthy broiler chickens after a single oral administration at 5xa0mg/kg bw. Then, the model extrapolation from healthy chickens to those infected with Pasteurella multocidaones was performed. The healthy model was validated through a comparison of predicted and previously published concentrations, which indicated that the healthy PBPK model had good predictive ability in plasma, lung, muscle, liver, and kidney, especially at the later sampling time points. Multiple dosing of administration was incorporated into the healthy and infected models. In addition, a Monte Carlo simulation (MCS) included 1000 iterations was further incorporated into both models to predict the withdrawal times of danofloxacin in healthy and infected chickens, which were estimated to be 3 and 2xa0days, respectively.

Pharmacokinetic interactions of flunixin meglumine and doxycycline in broiler chickens

Flunixin meglumine (FLM), a nonsteroidal anti-inflammatorydrug (NSAID) which functions through inhibiting cyclooxygen-ase that catalyses the incorporation of molecular oxygen intoarachidonic acid to produce prostanoids, has been licensed to usefor beef cattle, dairy cattle and horses (CVMP, 2000). It is alsoapproved to treat respiratory diseases and relieve pains in poultryin China. Doxycycline is a tetracycline antibiotic with a broadantimicrobial spectrum, including gram-negative and gram-positive bacteria, rickettsias, chlamydias, mycoplasmas, spiro-chaetes and some protozoa (Riond & Riviere, 1988). It is widelyused for treatments of respiratory infections in poultry.With the development of intensive poultry industry, poultry,especially broiler chickens, are increasingly vulnerable to beinjured due to squeeze afterwards suffering from inflammationand pains. Given animal welfare, it is of practical importance tocombine broad spectrum antibiotics and NSAIDs such asdoxycycline and FLM for anti-inflammatory. However, whetherit is feasible needs to be investigated. The purpose of the presentwork was to study the pharmacokinetics and possible interac-tions of doxycycline and flunixin in broiler chickens.All animal experiments were performed in accordance withthe approved IACUC protocols in South China AgriculturalUniversity. Thirty healthy broiler chickens (Hubbard·Hubbard)of both sexes, 35–40 days old, weighing 1.5–1.8 kg, wereequally divided into three groups. Birds in the first two groupswere intravenously administered with single dose of FLM(5 mg⁄kg, calculated as flunixin) and doxycycline hyclate(20 mg⁄kg, calculated as doxycycline base) via left leg vein,respectively. Those in the third group received simultaneousintravenous administrations with single dose of FLM (5 mg⁄kgb.w.) and doxycycline (20 mg⁄kg b.w.) via leg veins on bothsides. The flunixin dose of 5 mg⁄kg was selected according to thereports of Hocking et al. (2005) and Musser (2010). Bloodsamples (about 2.0 mL) were collected from wing vein at 0(before administration), 5, 10, 20 and 30 min and 1, 2, 4, 6, 8,12, 24, 36, 48 and 60 h after injection. Plasma was separatedby centrifugation at 1268 g for 10 min and then stored at)20 C.Doxycycline concentrations in plasma were determined usinga high-performance liquid chromatography (HPLC) method withultraviolet detection based on our previous report (Yang et al.,2012). Briefly, 0.5 mL plasma samples were mixed with 400 lLbuffer⁄EDTA and 100 lL 20% perchloric acid and vortexed for3 min followed by centrifugation at 12 000 g for 15 min. Then,50 lL of supernatant was injected onto a Hypersil BDS-C18column (4.6 · 250 mm, 5 lm; Elite analytical instruments Co.,Ltd., Dalian, China) which was kept at 30 C. The mobile phaseconsisted of acetonitrile and 0.01 mol⁄L trifluoroacetic acid (3:7,v⁄v) at a flow rate of 1 mL⁄min. A Dionex UltiMate 3000 SeriesHPLC system (Dionex Corporation, Sunnyvale, CA, USA) con-sisting of quaternary pump, vacuum degasser, column compart-ment, automatic sampler and ultraviolet detector was used, andthe wavelength was set at 350 nm. The limits of detection (LOD)and quantitation (LOQ) for doxycycline based on a signal-to-noiseratio>3and>10 were0.05and0.1 lg⁄mL, respectively.Flunixin was also determined using an HPLC methodaccording to the report of Ogino et al. (2005). Samples wereprepared by adding 0.5 mL of plasma to 150 lL1

Multi-Residue Determination of Eight Anabolic Steroids by GC-MS in Muscle Tissues from Pigs

A gas chromatography-mass spectrometry (GC-MS) method to determine eight anabolic steroids (diethylstilbestrol, methyltestosterone, norethindrone, 17α-ethynylestradiol, estradiol, 6α-methyl-17α-hydroxy-progesterone, estradiol benzoate, and chlormadinone acetate) was developed. Muscle samples were extracted with liquid-liquid extraction and clean-up was performed in two steps, the extracts obtained were derivatized with heptafluorbutyric (HBF) anhydride and analyzed by GC-MS. In the above method, the linear scope was 2.5-50 μg kg^(-1). The range of the recoveries was 78.5-148% for diethylstilbestrol, 70.8-109% for methyltestosterone, 69.8-87.2% for norethindrone, 67.7-120% for 17α-ethynylestradiol, 82.8-103% for estradiol, 70.3-99.2% for 6α-methyl-17α-hydroxy-progesterone, 73.0-104% for estradiol benzoate, and 72.9- 91.8% for chlormadinone acetate. The range of the coefficients of variation within batches was 0.4-12%; the range of the coefficients of variation between batches was 6.4-11%. The limit of detections and the detection capability were 0.99 and 3.30 μg kg^(-1) for diethylstilbestrol, 1.05 and 3.50 μg kg^(-1) for methyltestosterone, 1.19 and 3.97 μg kg^(-1) for norethindrone, 0.94 and 3.13 μg kg^(-1) for 17α-ethynylestradiol, 1.45 and 4.83 μg kg^(-1) for estradiol, 1.56 and 5.20 μg kg^(-1) for 6α-methyl-17α-hydroxy-progesterone, 1.92 and 6.40 μg kg^(-1) for estradiol benzoate, and 2.41 and 8.03 μg kg^(-1) for chlormadinone acetate, respectively. These results showed that the method was widely available, accurate, and sensitive.

In vivo activity of cefquinome against Riemerella anatipestifer using the pericarditis model in the duck

Cefquinome is a fourth-generation cephalosporin with broad-spectrum antibacterial activity, including activity against enteric gram-negative bacilli such as Riemerella anatipestifer. The pericarditis model was used to examine the pharmacodynamic characteristics of cefquinome against R. anatipestifer. Serum levels of cefquinome following the administration of different doses were determined by LC-MS/MS. Ducks with ca. 10(6) CFU/mL at the initiation of therapy were treated with cefquinome at doses that ranged from 0.0156 to 2 mg/kg of body weight/day (in 3, 6, 12, or 24 divided doses) for 24 h. The percentage of a 24-h dosing interval that the unbound serum cefquinome concentrations exceeded the MIC (fT > MIC) were the pharmacokinetic (PK)-pharmacodynamic (PD) parameter that best correlated with efficacy (R(2) 86.3% for R. anatipestifer, compared with 58.9% for the area under the concentration-time curve/MIC and 10.6% for peak/MIC). A sigmoid Emax model was used to estimate the magnitudes of the %fT > MIC associated with net bacterial stasis, a 1-log10 CFU reduction from baseline, and a 2-log10 CFU reduction from baseline; the corresponding values were (22.5 ± 1.3) %, (35.2 ± 4.5) %, and (42.4 ± 2.7) %. These data showed that treatment with cefquinome results in marked antibacterial effects in vivo against R. anatipestifer and that the hosts immunity may also play a key role in the anti-infective therapy process.