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.

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 (Cmax) were 6.15 μg/mL (serum) and 1.15 μg/mL (TCF) after IM administration. The elimination half-lives (t1/2β) 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 AUCTCF/AUCserum (%) 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 Emax model; AUC24h/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 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.

The purpose of the study was to investigate the pharmacokinetics of cefquinome in plasma and milk samples of lactating Chinese Holstein following a single intramammary administration into one quarter at the dose of 75 mg. Residue depletion of cefquinome in milk administrated at one quarter following three consecutive infusions at the same dose were also carried out. Cefquinome concentrations in plasma and milk were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental analysis was used to obtain the pharmacokinetic parameters of cefquinome. Following the single treatment, cefquinome wasn't detected in any of the plasma samples. The concentration of cefquinome in milk reached peaked values (Cmax) of (599.00±322.00) μg mL−1 at 2 h after administration (Tmax), elimination half-life (t1/2λz) was (4.63±0.26) h, area under the concentration-time curve (AUC0-∞) was (4890.19±1906.98) μg mL−1 h, and mean residence time (MRT) was (6.03±2.27) h. In residue depletion study, cefquinome concentrations in 5 out of 6 milk samples at 72 h were lower than the maximum residue limit fixed by the European regulatory agency (20 μg kg−1 for cefquinome) and cefquinome still could be detected in milk of treated quarters at 120 h post-treatment. The maximum concentration (Cmax) of cefquinome in milk from treated quarters was (486.50±262.92) μg mL−1 and arrived at 6 h after administration (Tmax), elimination half-life (t1/2λz) was (6.30±0.76) h, area under the concentration-time curve (AUC0-∞) was (44747.79±11434.43) μg mL−1 h, and mean residence time (MRT) was (10.09±1.40) h. This study showed that cefquinome has the feature of poor penetration into blood and was eliminated quickly from milk in lactating cows after intramammary administration.