Dongping Zeng

Pharmacokinetics of mequindox and one of its major metabolites in chickens after intravenous, intramuscular and oral administration.

Pharmacokinetics of mequindox and one of its major metabolites (M) was determined in chickens after intravenous (i.v.), intramuscular (i.m.) and oral administration of mequindox at a single dose of 10 (i.v. and i.m.) or 20 mg/kg b.w. (oral). Plasma concentration profiles were analyzed by a non-compartmental pharmacokinetic method. Following i.v., i.m. and oral administration, the areas under the plasma concentration-time curve (AUC(0-∞)) were 0.71±0.15, 0.67±0.21, 0.25±0.10 μg h/mL (mequindox) and 37.24±7.98, 36.40±9.16, 86.39±16.01 μg h/mL (M), respectively. The terminal elimination half-lives (t(1/2λz)) were determined to be 0.15±0.06, 0.21±0.09, 0.49±0.23 h (mequindox) and 5.36±0.86, 5.39±0.52, 5.22±0.35 h (M), respectively. The bioavailabilities (F) of mequindox were 89.4% and 16.6% for i.m. and oral administration. Steady-state distribution volume (V(ss)) of 1.20±0.34 L/kg and total body clearance (Cl(B)) of 13.57±2.16 L/kg h were determined for mequindox after i.v. dosing. After single i.m. and oral administration, peak plasma concentrations (C(max)) of 3.04±1.32, 0.36±0.13 μg/mL (mequindox) and 3.81±0.92, 5.99±1.16 μg/mL (M) were observed at t(max) of 0.08±0.02, 0.32±0.12 h (mequindox) and 0.66±0.19, 6.67±1.03 h (M), respectively. The results showed that mequindox was rapidly absorbed after i.m. or p.o. administration and most of mequindox was transformed to metabolites in chickens, with much higher C(max)s and AUCs of metabolite (M) than those of mequindox in plasma.

Simultaneous determination of quinoxaline-1,4-dioxides in feeds using molecularly imprinted solid-phase extraction coupled with HPLC

A simple, selective, and reproducible molecularly imprinted SPE coupled with HPLC method was developed for monitoring quinoxaline-1,4-dioxides in feeds. Molecularly imprinted polymers were synthesized in methanol using mequindox (MEQ) as template molecule and acrylamide as functional monomer by bulk polymerization. Under the optimum SPE conditions, the novel polymer sorbents can selectively extract and enrich carbadox, MEQ, quinocetone, and cyadox from a variety of feeds. The molecularly imprinted SPE cartridge was better than nonimprinted, C(18) , and HLB cartridges in terms of both recovery and precision. Mean recoveries of four quinoxaline-1,4-dioxides from six kinds of feeds spiked at 1.0, 10, and 100 mg/kg ranged between 75.2 and 94.7% with RSDs of less than 10%. The decision limits (CCαs) and the detection capabilities (CCβs) of four analytes were 0.15-0.20 mg/kg and 0.44-0.56 mg/kg, respectively. The class selectivity of the polymers was evaluated by checking three drugs with different molecular structures to that of MEQ.

Pharmacokinetics of florfenicol in crucian carp (Carassius auratus cuvieri) after a single intramuscular or oral administration

The pharmacokinetics of florfenicol (FF) was studied in plasma after a single dose (40 mg/kg) of intramuscular (i.m.) or oral gavage (p.o.) administration to crucian carp (Carassius auratus cuvieri) in freshwater at 25 °C. Ten fish per sampling point were examined after treatment. The data were fitted to two-compartment open models follow both routes of administration. The estimates of total body clearance (CL(b) ), volume of distribution (V(d) /F), and absorption half-life (T(1/2(ka)) ) were 0.067 L/h/kg and 0.145 L/h/kg, 2.21 L/kg and 1.04 L/kg, 2.75 and 1.54/h following i.m. and p.o. administration, respectively. After i.m. injection, the elimination half-life (T(1/2(β)) ) was calculated to be 38.2h, the maximum plasma concentration (C(max) ) to be 16.82 μg/mL, the time to peak plasma FF concentration (T(max) ) to be 1.50 h, and the area under the plasma concentration-time curve (AUC) to be 597.4 μg/mL·h. Following p.o. administration, the corresponding estimates were 2.17 h, 29.32 μg/mL, 1.61 h, and 276.1 μg/mL·h.

Plasma and tissue pharmacokinetics of danofloxacin in healthy and in experimentally infected chickens with Pasteurella multocida

Danofloxacin is a synthetic antibiotic of the fluoroquinolone group developed specifically for use in veterinary medicine. The spectrum of antimicrobial activity of danofloxacin is wide and includes most Gram-negative bacteria, some Gram-positive bacteria and Mycoplasma spp. Owing to its high concentration in animal lung (Apley & Upson, 1993; Friis, 1994; Knoll et al., 1999), danofloxacin has been widely used in China for the control of respiratory bacterial infections in chicken, bovine and swine. Some studies have shown that the pharmacokinetics and tissue distribution of drugs can be influenced by the pathophysiological changes during an infection (Van Miert, 1990; Zeng & Feng, 1997; Huang et al., 2003). Therefore, it is important to evaluate the pharmacokinetics and tissue distribution of the drug in infected animals as well as in healthy animals. The pharmacokinetics and distribution of danofloxacin into the tissues have been evaluated in experimentally infected pigs with Actinobacillus pleuropneumoniae or Salmonella typhimurium (Friis & Nielsen, 1997; Lindecrona et al., 2000). A pharmacokinetic study of danofloxacin in febrile goats following repeated administration of endotoxin was also reported by Ismail (2006). However, little information is available about danofloxacin distribution to tissues in chickens infected with Avian Pateurellosis. The objective of this study was to describe and compare the pharmacokinetic variables of danofloxacin in healthy chickens and chickens infected with Pasteurella multocida. This study was carried out in 174 80-day-old healthy Lingnan yellow broiler chickens (Gallus gallus domesticus) (free from Pasteurella multocida, mean body weight 1.76 ± 0.33 kg). One hundred and forty-four of 174 chickens were randomly divided into two groups of 72 animals each, one group to study the danofloxacin pharmacokinetics and tissue distribution in healthy chickens while the other group to study infected chickens, with Pasteurella multocida. Eighteen of 174 chickens were used for observation of gross and microscopic lesions after infection and other 12 chickens were used as negative control to obtain blank plasma and tissue samples, respectively. The chickens were provided a drug-free pelleted diet and given water ad libitum in this study except for fasting during 12 h before drug administration to 4 h after drug administration. All procedures involving animals complied with the local animal ethics regulations and were conducted under the close supervision and guidance of an experienced veterinarian. The 72 chickens used for the infection study were infected with Pasteurella multocida (Isolate C48-1, China Institute of Veterinary Drug Control, Beijing, China) according to Huang et al. (2003). Each chicken in the infected group was inoculated with 3·10 CFU ⁄ mL bacterial suspension by injection into pectoral muscle at a volume of 1 mL ⁄ kg b.w. After inoculation, the clinical signs, the change of cloacal temperature, the serum biochemical indices of infected chickens were recorded. Necropsy, histological examination and isolation of the pathogen were also carried out to validate the success of the experimental infection. Danofloxacin methanesulphonate raw material (96.7%. lot 990918) and danofloxacin methanesulphonate standard (99.7%, 981018) were kindly provided by Guangdong Yantang Veterinary Medicine Factory (Guangzhou, China). Into the crop of the infected chickens (12 h after inoculation) and healthy chickens, 0.5% danofloxacin solution (prepared by dissolving 3.2805 g of danofloxacin methanesulphonate raw material in 500 mL water) was orally administrated by oral gavage at a dosage of 5 mg ⁄ kg b.w. In healthy or infected groups, 72 chickens were randomly divided into 6 sub-groups, 12 animals in each sub-group. One chicken was euthanized by cervical dislocation at each sampling time after drug administration (0.5, 1, 2, 4, 6, 10, 16, 24, 36, 48, 60 and 72 h) in each sub-group. Whole blood (plus heparin sodium, average molecular weight 15000) from chickens was centrifuged for 10 min at 1370 g and the supernatant plasma were collected and stored at )20 C until analysis within J. vet. Pharmacol. Therap. 34, 101–104. doi: 10.1111/j.1365-2885.2010.01223.x SHORT COMMUNICATION

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.

Liquid chromatography tandem mass spectrometry for the simultaneous determination of mequindox and its metabolites in porcine tissues

A rapid liquid chromatography tandem mass spectrometric method was developed for the simultaneous determination of mequindox and its five metabolites (2-isoethanol mequindox, 2-isoethanol 1-desoxymequindox, 1-desoxymequindox, 1,4-bisdesoxymequindox, and 2-isoethanol bisdesoxymequindox) in porcine muscle, liver, and kidney, fulfilling confirmation criteria with two transitions for each compound with acceptable relative ion intensities. The method involved acid hydrolysis, purification by solid-phase extraction, and subsequent analysis with liquid chromatography tandem mass spectrometry using electrospray ionization operated in positive polarity with a total run time of 15 min. The decision limit values of five analytes in porcine tissues ranged from 0.6 to 2.9 μg/kg, and the detection capability values ranged from 1.2 to 5.7 μg/kg. The results of the inter-day study, which was performed by fortifying porcine muscle (2, 4, and 8 μg/kg), liver, and kidney (10, 20, and 40 μg/kg) samples on three separate days, showed that the accuracy of the method for the various analytes ranged between 75.3 and 107.2% with relative standard deviation less than 12% for each analyte.

Plasma and tissue pharmacokinetics of marbofloxacin in experimentally infected chickens with Mycoplasma gallisepticum and Escherichia coli.

The plasma and tissue pharmacokinetics of marbofloxacin in chickens experimentally infected with Mycoplasma gallisepticum and Escherichia coli were studied. Marbofloxacin was given to 66 infected chickens by oral administration at a dosage of 5 mg/kg b.w., once a day for three days. Plasma, brain, kidney, liver, lung, muscle and trachea were collected and marbofloxacin concentrations were analyzed by a high performance liquid chromatography method. In the infected chickens, maximal marbofloxacin concentrations in plasma, brain, kidney, liver, lung, muscle and trachea were 1.84, 1.33, 7.35, 5.61, 3.12, 2.98, and 4.51 g/mL (g); the elimination half-lives of marbofloxacin were 6.8, 2.74, 9.31, 8.45, 9.55, 11.53 and 5.46 h for plasma, brain, kidney, liver, lung, muscle and trachea, respectively. AUC were calculated to be 9.68, 8.04, 45.1, 27.03, 20.56, 19.47, and 32.68 μg/mL (g) for plasma, brain, kidney, liver, lung, muscle and trachea, respectively. Marbofloxacin concentration in tissues except for brain exceeded marbofloxacin concentration in plasma, with AUC(tissue) /AUC(plasma) ranging from 2.01 to 4.66 and Peak(tissue) /Peak(plasma) ranging from 1.62 to 3.99. The results showed that a marbofloxacin dosage of 5 mg/kg administered orally at 24 h intervals may provide successful treatment of chicken with MG and E. coli infection.

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