A chronic toxicity study of cyadox in Wistar rats

Wang, Xu; He, Q.; Wang, Yulian; Ihsan, Awais; Huang, Lingli; Wei, Zhou; Su, Shijia; Liu, Zhenli; Zhang, Yuan

doi:10.1016/j.yrtph.2010.11.004

Cited by 38 publications

(32 citation statements)

References 36 publications

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“…Cyadox (CYA) is a synthetic 1,4-dioxide quinoxaline antimicrobial agent for use in food-producing animals, including pigs and chicken (Wang et al, 2005;Ding et al, 2006a;. CYA is less toxic than its congeners, olaquindox and carbadox Huang et al, 2010;Wang et al, 2011). However, excessive exposure to CYA has been reported to cause adverse effect on mouse and human microflora (Hao et al, 2013;Huang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

Huang

Lin

Zhou

et al. 2015

Food Additives & Contaminants: Part A

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Physiologically based pharmacokinetic (PBPK) models are powerful tools to predict tissue distribution and depletion of veterinary drugs in food animals. However, most models only simulate the pharmacokinetics of the parent drug without considering their metabolites. In this study, a PBPK model was developed to simultaneously describe the depletion in pigs of the food animal antimicrobial agent cyadox (CYA), and its marker residue 1,4-bisdesoxycyadox (BDCYA). The CYA and BDCYA sub-models included blood, liver, kidney, gastrointestinal tract, muscle, fat and other organ compartments. Extent of plasma-protein binding, renal clearance and tissue-plasma partition coefficients of BDCYA were measured experimentally. The model was calibrated with the reported pharmacokinetic and residue depletion data from pigs dosed by oral gavage with CYA for five consecutive days, and then extrapolated to exposure in feed for two months. The model was validated with 14 consecutive day feed administration data. This PBPK model accurately simulated CYA and BDCYA in four edible tissues at 24-120 h after both oral exposure and 2-month feed administration. There was only slight overestimation of CYA in muscle and BDCYA in kidney at earlier time points (6-12 h) when dosed in feed. Monte Carlo analysis revealed excellent agreement between the estimated concentration distributions and observed data. The present model could be used for tissue residue monitoring of CYA and BDCYA in food animals, and provides a foundation for developing PBPK models to predict residue depletion of both parent drugs and their metabolites in food animals.

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Section: Introductionmentioning

confidence: 99%

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

Huang

Lin

Zhou

et al. 2015

Food Additives & Contaminants: Part A

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“…Cited from (Chen et al, 2013;Huang et al, 2015bHuang et al, , 2015cLi et al, 2014aLi et al, , 2014bLiu et al, 2008Liu et al, , 2009Liu et al, , 2010aLiu et al, , 2010bLiu et al, , 2010cLiu et al, , 2011aLiu et al, , 2011bLiu & Sun, 2013;Mu et al, 2014;Tang et al, 2012;Wang et al, 2016b;Yang et al, 2013a;Zheng et al, 2011). marked as less genotoxicity than other kinds Wang et al, , 2011b. Based on the same quinoxaline structure and different toxicity of QdNOs with different side chains, it was indicated that the side chains played crucial roles in their toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Quinoxaline 1,4-dioxide derivatives (QdNOs), consisting of one or two acyclic chain moieties combined with a quinoxaline ring, are a great family with the wide range of biological properties such as antibacterial, antitubercular, anticancer, anticandida, antiprotozoal and growthpromoting activities (Carta et al, 2005;Ihsan et al, 2011;Vicente et al, 2009;Wang et al, 2011bWang et al, , 2015c. Carbadox (CBX, methyll-3-(2-quinoxalinyl methylene) carbazate-N1,N4-dioxide) and olaquindox (OLA, 2-(N-2 0 (hydroxymethyl) carboamoyl)-3-methylquinoxaline N1,N4-dioxide) are members of the QdNO family.…”

Section: Introductionmentioning

confidence: 99%

“…CYA was thought to be a potential replacement for OLA in China (Huang et al, 2016). Compared with other QdNOs, CYA showed good safety in mutagenicity studies (Huang et al, 2016;Ihsan et al, 2013aIhsan et al, , 2013b, 90-day feeding studies , teratogenicity and reproduction studies , chronic studies (Wang et al, 2011b) and carcinogenicity studies (Sevcik, 1986). On the other hand, it has also been shown that QdNOs have potential phototoxic and photoallergic effects in farm workers.…”

Section: Introductionmentioning

confidence: 99%

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The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

Wang

Martínez

Cheng

et al. 2016

Drug Metabolism Reviews

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Quinoxaline 1,4-dioxide derivatives (QdNOs) have been widely used as growth promoters and antibacterial agents. Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), cyadox (CYA) and mequindox (MEQ) are the classical members of QdNOs. Some members of QdNOs are known to cause a variety of toxic effects. To date, however, almost no review has addressed the toxicity and metabolism of QdNOs in relation to oxidative stress. This review focused on the research progress associated with oxidative stress as a plausible mechanism for QdNO-induced toxicity and metabolism. The present review documented that the studies were performed over the past 10 years to interpret the generation of reactive oxygen species (ROS) and oxidative stress as the results of QdNO treatment and have correlated them with various types of QdNO toxicity, suggesting that oxidative stress plays critical roles in their toxicities. The major metabolic pathways of QdNOs are N→O group reduction and hydroxylation. Xanthine oxidoreductase (XOR), aldehyde oxidase (SsAOX1), carbonyl reductase (CBR1) and cytochrome P450 (CYP) enzymes were involved in the QdNOs metabolism. Further understanding the role of oxidative stress in QdNOs-induced toxicity will throw new light onto the use of antioxidants and scavengers of ROS as well as onto the blind spots of metabolism and the metabolizing enzymes of QdNOs. The present review might contribute to revealing the QdNOs toxicity, protecting against oxidative damage and helping to improve the rational use of concurrent drugs, while developing novel QdNO compounds with more efficient potentials and less toxic effects.

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“…It is effective against a number of the pathogenic bacteria in food‐producing animals (Fan, Yuan, & Wang, ; Huang et al., ), and could promote the average daily gain and feed conversion ratio, and prevent Escherichia coli infection in pigs and chickens (Ding, Yuan, Wang, Zhu, & Fan, ; Huang & Yuan, ; Wang, Yuan, Zhu, Ding, & Fan, ). Toxicology studies showed that CYA was much safer than olaquindox (OLA) and carbadox (CBX), well‐known members of the quinoxaline family but banned or strictly limited in food‐producing animals due to their potential toxicities(He et al., ; Huang et al., ; Ihsan et al., ; Wang, Fang, et al., ; Wang, He, et al., ). The food safety of CYA in animal products needs to be investigated to assure the health of the consumers.…”

Section: Introductionmentioning

confidence: 99%

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

Huang

Qiu

Sun

et al. 2017

Vet Pharm & Therapeutics

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The tissue kinetics of cyadox, an antibacterial agent used in food animals, and its major metabolites in pigs, chickens, and carp were investigated followed by a complete dietary exposure assessment to evaluate the food safety of cyadox. Cyadox and its major metabolites, bisdeoxycyadox (Cy1), 4-desoxycyadox (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), quinoxaline-2-carboxylic acid (Cy6), and 2-hydrometh yl-3-hydroxy-quinoxaline (Cy12), were simultaneously quantitated with a highperformance liquid chromatography−ultraviolet (HPLC-UV) method. Pigs, chickens, and carp were fed with 150 mg/kg cyadox in feed for consecutive 60, 40, and 30 days, respectively. The residue amount of cyadox and its major metabolites in liver, kidney, muscle, and fat (skin) tissues was determined. Cy2 was below the limit of quantitation even at the withdrawal time of 6 hr, cyadox, Cy4, Cy6, and Cy12 could be detected at 6-24 hr with low level less than 50 μg/kg. By contrast, Cy1 persisted for 3 days in the kidney of pigs and chickens, and in the liver of carp. Based on these residue depletion data and previous toxicology results, the global estimated chronic dietary exposure assessment of cyadox for general population was conducted, indicating a zero withdrawal time (WDT) may be appropriate for cyadox in food animals when used in feed for prolonged administration. These results provide analytical techniques and safety standards suitable for residue monitoring of cyadox in food animals.

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A chronic toxicity study of cyadox in Wistar rats

Cited by 38 publications

References 36 publications

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

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