Huanzhong Ding

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.

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 10 mg/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.

Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection

ABSTRACT Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10 CFU reduction from baseline, and a 1-log10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused by S. aureus.

Pharmacokinetics of Quinocetone and Its Major Metabolites in Swine After Intravenous and Oral Administration

Abstract Pharmacokinetics of cyadox (CYX) and its major metabolites in healthy swine was investigated in this paper. 1,4-Bisdesoxycyadox (BDCYX), cyadox-1-monoxide (CYX-1-O) and quinoxaline-2-carboxylic acid (QCA), three main metabolites of cyadox, were synthesized by College of Science, China Agricultural University. Cyadox (CYX) was administered to 8 healthy cross-bread swine intravenously (i.v.) and orally (p. o.) at a dosage of 1 mg kg−1 body weight and 40 mg kg−1 body weight respectively in a randomized crossover design test with 2-wk washout period. A sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the determination of cyadox and its major metabolites in plasma. CYX and its major metabolites BDCYX, and CYX-1-O can be detected after intravenous administration of cyadox while CYX and its metabolites BDCYX, CYX-1-O and QCA can be detected after oral administration of CYX. Plasma concentration vs. time profiles of CYX and its major metabolites were analyzed by non-compartmental pharmacokinetic method. Following i.v. administration, the areas under the plasma concentration-time curve (AUC0-∞) were (0.38±0.03) μg mL−1 h (CYX), (0.018±0.002) μg mL−1 h (BDCYX) and (0.17±0.02) μg mL−1 h (CYX-1-O), respectively. The terminal elimination half-lives (t1/2lz) were determined to be (0.93±0.07) h (CYX), (1.45±0.04) h (BDCYX), and (0.92±0.04) h (CYX-1-O), respectively. Steady-state distribution volume (Vss) of (2.14±0.11) L kg−1 and total body clearance (CL) of (2.84±0.19) L h−1 kg−1 were determined for CYX after i.v. dosing. The bioavailability (F) of CYX was 2.85% for oral administration. After single i.v. administration, peak plasma concentrations (Cmax) of (1.08±0.06) μg mL−1 (CYX), (0.0068± 0.0004) μg mL−1 (BDCYX) and (0.25±0.03) μg mL−1 (CYX-1-O) were observed at Tmax of 0.033 h (CYX), 1 h (BDCYX) and 0.033 h (CYX-1-O), respectively. The main pharmacokinetic parameters after p.o. administration were as follows: AUC0-∞ were (0.42±0.04) μg mL−1 h (CYX), (1.38±0.14) μg mL−1 h (BDCYX), (0.59±0.02) μg mL−1 h (CYX-1-O) and (1.48±0.09) μg mL−1 h (QCA), respectively. t1/2lz were (4.77±0.33) h (CYX), (5.77±0.56) h (BDCYX), (4.12±0.28) h (CYX-1-O), and (8.51±0.39) h (QCA), respectively. After p.o. administration, Cmaxs of (0.033±0.002) μg mL−1 (CYX), (0.22±0.03) μg mL−1 (BDCYX), (0.089±0.005) μg mL−1 (CYX-1-O), and (0.17± 0.01) μg mL−1 (QCA) were observed at Tmax of (7.38±0.33) h (CYX), (7.25±0.31) h (BDCYX), (7.38±0.33) h (CYX-1-O), and (7.25±0.31) h (QCA), respectively. The results showed that CYX was slowly absorbed after oral administration and most of CYX was transformed to its metabolites in swine. The area under plasma concentration-time curve (AUC0-∞) of metabolites were higher than that of CYX after p.o. administration, and the elimination half-lives (t1/2lz) of QCA were longer than those of CYX, CYX-1-O, and BDCYX after oral administration.

Metabolism of mequindox and its metabolites identification in chickens using LC-LTQ-Orbitrap mass spectrometry

Mequindox (MEQ), 3-methyl-2-quinoxalinacetyl-1,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial and feed additive. Its toxicities have been reported to be closely related to its metabolism. To understand more clearly the metabolic pathways of MEQ, its metabolism in chickens was studied using liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap (LC-LTQ-Orbitrap) mass spectrometry. The structures of the MEQ metabolites and their product ions were easily and reliably characterized based on the accurate MS-squared spectra and known structure of MEQ. Twenty-four metabolites were detected in chicken plasma, bile, faeces, and tissues, of which 12 were detected in vivo for the first time. The major metabolic pathways reported previously for in vitro metabolism of MEQ in chicken microsomes were confirmed in this study, including N→O group reduction, carbonyl reduction, and methyl mono-hydroxylation. In addition, deacetylation and acetyl-hydroxylation of MEQ were shown to be important metabolic pathways. Collectively, these data contribute to our understanding of the in vivo metabolism of MEQ.

Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.

Pharmacokinetics and ex vivo pharmacodynamics of cefquinome in porcine serum and tissue cage fluids.

A tissue cage (TC) model was used to evaluate the pharmacokinetics and ex vivo pharmacodynamics of cefquinome after intravenous (IV) and intramuscular (IM) administration to piglets at 2 mg/kg bodyweight. The mean values of area under the concentration-time curve (AUC) were 21.28 (IV) and 21.37 (IM) μg h/mL for serum, and 17.40 (IV) and 16.57 (IM) μg h/mL for TC fluid (TCF), respectively. Values of maximum concentration (C(max)) were 6.15 μg/mL (serum) and 1.15 μg/mL (TCF) after IM administration. The elimination half-lives (t(1/2β)) in TCF (10.63 h IV and 11.81 h IM) were significantly higher than those in serum (2.33 h IV and 2.30 h IM) (P<0.05). The values of AUC(TCF)/AUC(serum) (%) after IV and IM administration were 82.4% and 80.7%, respectively. The ex vivo time-kill curves were established for serum and TCF samples using Escherichia coli ATCC 25922. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration values of cefquinome against E. coli were 0.030 and 0.060 μg/mL in Mueller-Hinton broth, and 0.032 and 0.064 μg/mL in both serum and TCF, respectively. The ex vivo growth inhibition data of TCF after IM administration were fitted to the sigmoid E(max) model; AUC(24h)/MIC was 35.01 h for bactericidal activity and 44.28 h for virtual eradication, respectively. The findings from this study suggest that cefquinome may be therapeutically effective in diseases of pigs caused by E. coli when used at a dose rate of 1.33 mg/kg administered every 24 h for organisms with MIC90⩽0.50 μg/mL.

Pharmacokinetics of mequindox and its metabolites in rats after intravenous and oral administration.

Pharmacokinetics of mequindox (MEQ) and its metabolites were determined in rats after intravenous (i.v.) and oral (p.o.) administration of MEQ at a single dose of 10 mg kg(-1) bodyweight. After both administrations, MEQ and five of its metabolites were quantified, except M4, whereas M1 and M2 were the predominant ones. The areas under the concentration-time curves (h ng mL(-1)) of MEQ, M1, M2, M3, M5 and M10 after i.v. administration were 7559±495, 6354±2761, 5586±2337, 1034±160, 2370±791 and 1813±622, respectively, whereas after p.o. administration, remained as 2809±40, 4361±3544, 4351±1046, 1444±814, 3864±305 and 1213±569, respectively. The elimination half-lives (h) of these compounds after i.v. administration were 3.48±0.80, 4.20±0.76, 6.25±2.41, 4.77±1.54, 4.69±1.62 and 16.89±5.15, respectively, and were 3.21±0.40, 3.66±1.06, 4.20±1.03, 8.91±5.99, 4.20±2.02 and 20.84±10.85 after p.o. administration, respectively. After p.o. administration, the bioavailability of MEQ was 37.16%. The results showed that MEQ was extensively metabolized in rats and rapidly absorbed after p.o. administration.

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

Tissue deposition and residue depletion of cyadox and its three major metabolites in pigs after oral administration.

Tissue deposition and residue depletion profiles of cyadox (Cyx) and its three major metabolites, including 1,4-bisdesoxycyadox (Cy1), 4-desoxycyadox (Cy2), and quinoxaline-2-carboxylic acid (QCA), in pigs after multiple oral administrations were determined. Thirty-five healthy adult pigs were randomly divided into seven groups and orally treated with Cyx at a dosage of 20 mg/kg of body weight for five consecutive days. Each group of five pigs was randomly slaughtered 12, 24, 72, 120, 168, 216, and 264 h after the last dosing, and tissue samples, including muscle, liver, kidney, and fat, were collected and analyzed via the liquid chromatography-tandem mass spectrometry method. The concentration-time data of Cyx and its three metabolites (Cy1, Cy2, and QCA) were analyzed with WinNonlin. Results showed that metabolites of Cyx were quickly generated in swine tissues and the concentrations of QCA in kidney were higher than those of Cyx and other metabolites in all edible tissues. These results provide further insight into the metabolism of Cyx and confirmation of the residue marker and target tissue of Cyx in pigs.