methyl-3-quinoxaline-2-carboxylic-acid and olaquindox

To estimate the consumer exposure to olaquindox (OLA) residues in porcine edible tissues, a physiologically based pharmacokinetic (PBPK) model for methyl-3-quinoxaline-2-carboxylic acid (MQCA), the marker residue of OLA, was developed in pigs based on the assumptions of the flow-limited distribution, hepatic metabolism, and renal excretion. The model included separate compartments corresponding to blood, muscle, liver, kidney, adipose, and an extra compartment representing the remaining carcass. Physiological parameters were determined from literatures. Plasma protein binding, partition coefficients, and renal clearance for MQCA were determined in in vitro and in vivo studies. The metabolic conversion of OLA to MQCA was assumed as a simple, one-step process, and an apparent first-order rate constant (k) was employed to describe this metabolic process. The PBPK model was optimized and validated with plasma and tissue data from literatures and our study. Sensitivity analysis and Monte Carlo simulation were also implemented to estimate the influence of model parameters on the goodness of fit. When compared with the observed data, the PBPK model underestimated the MQCA level in all compartments at the early time points, whereas gave excellent predictions of MQCA concentration in porcine edible tissues at later time points. The correlation coefficients between the predicted and observed values were over 0.88. The consistency between the model predictions and the real residues of OLA in pigs proved the good applicability of our model in food safety risk assessment.

Topics: Absorption; Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Residues; Male; Models, Biological; Monte Carlo Method; Muscle, Skeletal; Quinoxalines; Swine

A residue depletion study was performed to investigate the tissue kinetics and tissue-plasma correlation of methyl-3-quinoxaline-2-carboxylic acid (MQCA), the marker residue of olaquindox (OLA), in pigs. Twenty-five pigs were randomly divided into a test and a control group. The former group was treated with 100 mg/kg OLA in its feed for 30 consecutive days, and the latter was given blank feed for the same period. One control and four treated animals were slaughtered at 0.5, 3, 10, 17, and 28 days post-medication. Muscle, liver, kidney, fat, and plasma samples were collected and analyzed using the validated high-performance liquid chromatography method (HPLC). Results showed that the tissue concentration of MQCA in the liver > kidney > fat > muscle, at almost all time points. The half-lives of MQCA in the muscle, liver, kidney, fat, and plasma were 12, 8, 15, 8, and 6 days, respectively. A withdrawal period of 38 days was calculated using the statistical method recommended by the European Medical Evaluation Agency (EMEA). Good correlations between tissue and plasma MQCA levels were found in the present study with correlation coefficients of more than 0.92. These correlations would be helpful in the routine monitoring of OLA in porcine tissues, without sacrificing the animals.

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Drug Residues; Female; Growth Substances; Kidney; Liver; Male; Muscles; Quinoxalines; Random Allocation; Swine; Tissue Distribution

A method is described for the quantitative determination of quinoxaline-2-carboxylic acid (QCA) and methyl-3-quinoxaline-2-carboxylic acid (MQCA), the metabolites that have been designated as the marker residues for the veterinary drugs, carbadox and olaquindox, respectively, in swine tissue. The method is suitable for use as a confirmatory method under EU National Surveillance Schemes. Porcine liver samples were subjected to protease digestion followed by liquid-liquid extraction. Further clean-up was performed by automated solid phase extraction (SPE) and was followed by a final liquid-liquid extraction step. Analysis was performed using a narrow bore column HPLC coupled to electrospray MS/MS, operated in positive ion mode. MS/MS product ions were monitored at m/z 102 and 75 amu for QCA, m/z 145 and 102 amu for MQCA and at m/z 106 and 152 amu for the d(4)-QCA and d(7)-MQCA internal standards, respectively. The method has been validated at 3.0, 10, 50 and 150 microg kg(-1) for both metabolites. The method performance characteristics-the decision limit (CCalpha) and the detection capability (CCbeta) have been determined for QCA at 0.4 and 1.2 microg kg(-1), respectively, and for MQCA at 0.7 and 3.6 microg kg(-1), respectively.

Topics: Animals; Biomarkers; Carbadox; Chromatography, Liquid; Drug Residues; Liver; Quinoxalines; Spectrometry, Mass, Electrospray Ionization; Swine