mequindox and quinocetone

The aim of this article is to get an overview of the metabolism of quinoxaline 1,4-di-N-oxides (QdNOs) used in food animals. The derivatives of QdNOs (carbadox, olaquindox, mequindox, quinocetone, and cyadox) are the potent synthetic antimicrobial agents that are used for improving the feed efficiency and controlling dysentery in food-producing animals. Studies have demonstrated that the toxicity of QdNOs is closely associated with the production of their metabolism, especially with the production of their reduced metabolites. To the best of our knowledge, no one has systematically compiled the metabolism data of QdNOs. Therefore, the metabolism of QdNOs in animals has been discussed in the review for the first time. These drugs undergo extensive metabolism prior to excretion. N-oxide group reduction is the major metabolic pathway of QdNOs. Moreover, the N1- and N4-oxide reductions of QdNOs by different reducing mechanisms are also described. Obvious differences in metabolic pathways for QdNOs were observed owing to the differences on the side chain of these drugs. Therefore, understanding the metabolic pathways of QdNOs in animals will provide the guides for further studies of metabolism and toxicology of these drugs, and will also provide abundant information for the food safety assessment.

Topics: Animals; Carbadox; Humans; Quinoxalines

Physiologically based pharmacokinetic (PBPK) models are scientific methods used to predict veterinary drug residues that may occur in food-producing animals, and which have powerful extrapolation ability. Quinocetone (QCT) and mequindox (MEQ) are widely used in China for the prevention of bacterial infections and promoting animal growth, but their abuse causes a potential threat to human health. In this study, a flow-limited PBPK model was developed to simulate simultaneously residue depletion of QCT and its marker residue dideoxyquinocetone (DQCT) in pigs. The model included compartments for blood, liver, kidney, muscle and fat and an extra compartment representing the other tissues. Physiological parameters were obtained from the literature. Plasma protein binding rates, renal clearances and tissue/plasma partition coefficients were determined by in vitro and in vivo experiments. The model was calibrated and validated with several pharmacokinetic and residue-depletion datasets from the literature. Sensitivity analysis and Monte Carlo simulations were incorporated into the PBPK model to estimate individual variation of residual concentrations. The PBPK model for MEQ, the congener compound of QCT, was built through cross-compound extrapolation based on the model for QCT. The QCT model accurately predicted the concentrations of QCT and DQCT in various tissues at most time points, especially the later time points. Correlation coefficients between predicted and measured values for all tissues were greater than 0.9. Monte Carlo simulations showed excellent consistency between estimated concentration distributions and measured data points. The extrapolation model also showed good predictive power. The present models contribute to improve the residue monitoring systems of QCT and MEQ, and provide evidence of the usefulness of PBPK model extrapolation for the same kinds of compounds.

Topics: Animals; Drug Residues; Models, Biological; Molecular Dynamics Simulation; Monte Carlo Method; Quinoxalines; Swine

Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects.

Topics: Adrenal Gland Diseases; Aldosterone; Antioxidants; Biotransformation; Cell Line; Cell Survival; Cytochrome P-450 CYP11B2; Humans; Oxidative Stress; Proanthocyanidins; Quinoxalines; RNA, Messenger; Steroid 11-beta-Hydroxylase

A novel porous molecularly imprinted monolithic capillary column (MIMCC) based on ternary porogen was synthesized by in situ technique with sulfaquinoxaline as the template molecule. The characteristics of the MIMCC were investigated by scanning electron microscopy, infrared spectrum, thermogravimetric analysis and solvent resistance test. The saturated adsorption amount of sulfaquinoxaline on MIMCC was 2.7 times over that on the non-imprinted monolithic capillary column (NIMCC). The MIMCC also exhibited good enrichment ability to its analogs and the enrichment factors were 46-211 for five antimicrobials. High permeability and imprinting factors as well as good stability, reproducibility and long lifetime were obtained. An on-line method based on MIMCC solid-phase microextraction coupled with high-performance liquid chromatography was developed for the determination of trace antimicrobials in complex samples. The good linearity for sulfametoxydiazine, sulamethoxazole and sulfaquinoxaline was 0.05-10 µg/L, the limits of detection (LODs) were 10.0-14.0 ng/L. The linear range for mequindox and quinocetone were 0.10-10.0 µg/L, the LODs were 20.0-27.0 ng/L respectively. The recoveries were 71.0-108.2% with relative standard deviation of 1.6-8.5%, correspondingly. The results showed that MIMCC could effectively enrich antimicrobials from complex matrices. The on-line method based on MIMCC and HPLC was selective, sensitive and convenient for trace determination of antimicrobials in complex samples.

Topics: Animals; Anti-Infective Agents; Chickens; Chromatography, High Pressure Liquid; Eggs; Food Analysis; Meat; Methacrylates; Microscopy, Electron, Scanning; Molecular Imprinting; Molecular Structure; Porosity; Quinoxalines; Reproducibility of Results; Silicon Dioxide; Solid Phase Extraction; Solvents; Spectrophotometry, Infrared; Sulfameter; Sulfaquinoxaline; Swine; Thermogravimetry

This report presents a UPLC-MS/MS method for determination of mequindox (MEQ), quinocetone (QCT) and their 11 metabolites in chicken and pork samples. Following extraction process with acetonitrile-ethyl acetate, acidulation, and re-extraction with ethyl acetate in turn, target analytes were further purified using C18 solid phase extraction (SPE) cartridges for UPLC-MS/MS analysis. Validation was processed with mean recoveries from 69.1% to 113.3% with intra-day relative standard deviation (RSD) <14.7%, inter-day RSD <19.2%, and limit of detection between 0.05 and 1.0 μg/kg for each analytes. The verified method was successfully applied to the quantitative determination of commercial samples. This developed procedure will help to control food animal products with MEQ and QCT residues, and facilitate further pharmacokinetic and residue studies of similar quinoxaline-1,4-dioxide veterinary drugs.

Topics: Animals; Anti-Bacterial Agents; Chickens; Chromatography, High Pressure Liquid; Food Contamination; Meat; Quinoxalines; Solid Phase Extraction; Swine; Tandem Mass Spectrometry; Veterinary Drugs

Olaquindox, one of the antimicrobial growth accelerants, is usually used as a feed additive in livestock production to improve feed efficiency. Due to health concerns over possible carcinogenic, mutagenic and photoallergenic effects of olaquindox on animals, the development of a simple, rapid and sensitive analytical method for determination of olaquindox is crucial and necessary.. In this paper, a novel and hydrophilic functionalised material of olaquindox-imprinted polymer was synthesised in aqueous solution by a surface molecular imprinting in combination with a sol-gel process. This imprinted material was characterised by Fourier transform infrared, scanning electron microscopy, and static and kinetic adsorption experiments, and results showed that it had good recognition and selective ability, and fast adsorption-desorption dynamics for olaquindox. Applying the prepared material as sorbent, a method of molecularly imprinted solid-phase extraction (MISPE) for separation and analysis of olaquindox residues in feeds coupled with HPLC was presented. Under the selected MISPE condition, the detection limit (S/N = 3) for olaquindox was 68.0 ng L(-1), the RSD for five replicate extractions of 50 µg L(-1) olaquindox was 9.8%. The blank chick feed samples spiked with olaquindox at 0.0025 and 0.010 mg g(-1) levels were extracted and determined by the developed method, with recoveries ranging from 90% to 96%.. This method was applied for enrichment and analysis of olaquindox in animal feed samples with good accuracy and repeatability. This study will provide a sensitive and fast method for the monitoring of olaquindox residues in foods.

Topics: Adsorption; Animal Feed; Animals; Anti-Infective Agents; Chickens; Chromatography, High Pressure Liquid; Food Additives; Gels; Kinetics; Limit of Detection; Microscopy, Electron, Scanning; Molecular Imprinting; Phase Transition; Polymers; Quinoxalines; Reproducibility of Results; Solid Phase Microextraction; Spectroscopy, Fourier Transform Infrared