肉鸡组织中癸氧喹酯检测方法及残留消除规律的研究
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摘要
癸氧喹酯(decoquinate)化学名为6-癸氧基-7-乙氧基-4-羟基-3-喹啉羧酸乙酯,属化学型喹啉类抗球虫药,主要用于预防肉仔鸡的球虫病。由于癸氧喹酯引入中国时间较短,有关癸氧喹酯在动物组织中的残留研究报道匮乏。本研究应用高效液相色谱-串联质谱法成功建立了肉鸡各组织中癸氧喹酯残留检测方法并分析癸氧喹酯在肉鸡体内的药动学特征及各组织中药物残留消除规律,为该药残留监控提供技术支持。目前该系列检测方法未见有研究报道。主要研究结果如下:
1、首次建立鸡血浆中癸氧喹酯的高效液相色谱-串联质谱测定方法。血浆样品经乙腈提取,氮气流吹干,采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,溶解残渣。采用电喷雾正离子电离模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在1 ng/mL～200 ng/mL范围内呈良好的线性关系,相关系数r~2均大于0.99;0.5、1、50 ng/mL 3个添加水平的回收率为85.0 %～96.9%,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为0.1 ng/mL,定量限为0.25 ng/mL。该方法简单快速、灵敏度高、选择性强,可用于鸡血浆中癸氧喹酯的药动学研究。
2、首次建立鸡肉、鸡肝和鸡肾组织中癸氧喹酯残留的高效液相色谱-串联质谱测定方法。样品经乙腈提取,正已烷脱脂,HLB固相萃取小柱净化;采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,电喷雾正离子电离模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在1.0、10、100μg/kg 3个添加水平的回收率均在75.5%～102.7%范围内,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为0.25μg/kg,定量限为0.5μg/kg。
3、首次建立鸡粪便中癸氧喹酯的高效液相色谱-串联质谱测定方法。样品经乙腈提取,HLB固相萃取小柱净化;采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,电喷雾正离子电离(ESI+)模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在5.0、10、100μg/kg 3个添加水平的回收率均在84.4%～100.1%范围内,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为2.5μg/kg,定量限为5μg/kg。
4、癸氧喹酯在肉鸡体内的药动学研究。选用10只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡体内的药物动力学研究。肉鸡口服给药癸氧喹酯的血浆药时数据符合一级吸收二室开放模型,主要药动学参数:吸收半衰期为2.614h,分布半衰期为3.944h,消除半衰期为19.334h,达峰时间长达15h,达峰浓度较低,为43.048ng/mL,药物在血浆中的平均滞留时间为47.065h。结果表明肉鸡口服癸氧喹酯后吸收慢且不完全,但吸收进入血浆中的癸氧喹酯消除缓慢。
5、癸氧喹酯在肉鸡体内的残留消除规律研究。选用36只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡胸肌、腿肌、肝脏和肾脏组织中的残留消除规律研究。结果表明:停药1d,癸氧喹酯在肝脏中残留量最高,达242μg/kg,在胸肌中最低为42μg/kg,停药3d后癸氧喹酯均从不同组织中迅速消除,且残留量均小于300μg/kg,远低于农业部235号公告所规定的2000μg/kg最高残留限量要求,证明现行的休药期5d是合理的。停药后0～5d,肝脏中癸氧喹酯的残留量在几种常见组织中均最高,肝脏可作为动物源性食品中癸氧喹酯残留监控靶组织。
6、鸡粪中癸氧喹酯残留消除规律的研究。选用6只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡粪便中的残留消除规律研究。结果表明:停药第1d癸氧喹酯的残留量就高达85.261 mg/kg,用药剂量的65.6%被排泄;停药2d后残留量迅速下降至2.835mg/kg,用药剂量的75.9%被排泄,表明癸氧喹酯在肉鸡体内吸收率低,生物利用度差,大部分药物未经吸收就直接通过粪便排出体外。粪便是癸氧喹酯在肉鸡体内的主要排泄途径。
7、福建省肉用鸡癸氧喹酯残留状况调查。分别随机选取了我省八地市70个肉鸡养殖场进行调查,共发放问卷70份,回收问卷70份,并按照随机原则在各设区、市市场遵照官方取样程序进行取样,共抽取了鸡肉样品和鸡肝样品各74份,并应用所建立的检测方法进行测定。结果表明:我省大部分养殖场从未使用过癸氧喹酯抗球虫药,抽检的148份鸡肉和鸡肝样品中也均未检出癸氧喹酯残留,表明癸氧喹酯在我省仍是一种有效的抗球虫药,具有很大的发展前景。
综上所述,本研究首次建立了鸡血浆、鸡肉、鸡肝、鸡肾及鸡粪中癸氧喹酯的高效液相色谱-串联质谱法,并阐明了鸡血浆中癸氧喹酯的药动学特征、鸡组织及鸡粪中癸氧喹酯的残留消除规律。研究结果不但为残留监控提供了重要的技术支撑,而且为我国修订癸氧喹酯残留限量标准和休药期提供了科学理论依据。
Decoquinate (6-ethyl-7-ethoxy-4-hydroxy-3-quinoline carboxylate) is a chemical quinolone coccidiostat as a in-feed prophylactic for broiler chickens to prevent and treat coccidiosis. Since it has not been widely used in China, few reports on decoquinate residue study in animal tissues were reported. In this research, the high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed for the determination of decoquinate residues in different chicken tissues and applied for the study on pharmacokinetics and residue elimination of decoquinate in chickens, which could provide technical support for the residue monitoring. The main results were as follows:
1. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residue in chicken plasma. The plasma sample was extracted with acetonitrile. The mobile phases consisted of 0.1% formic acid in acetonitrile and 0.1 % formic acid in water (78/22, v/v). The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:The calibration curve showed good linearity within the concentrations of 1 ng/mL～200 ng/mL with the correlation coefficient r~2>0.99. At the spiked levers of 0.5,1 and 50 ng/mL,the recoveries of decoquinate were 85.0%～96.9%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection (LOD) of decoquinate was 0.1 ng/mL and the limit of quantification (LOQ) was 0.25 ng/mL. The method was simple, sensitive and accurate which could be used for the pharmacokinetics study of decoquinate in chickens.
2. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residues in chicken meat, liver and kidney. The sample was extracted with acetonitrile, cleaned with hexane, and purified with HLB solid phase extraction (SPE) cartridge. The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:At the spiked levers of 1.0,10 and 100μg/kg,the recoveries of decoquinate were 75.5%～102.7%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection of decoquinate was 0.25μg/kg and the limit of quantification was 0.5μg/kg.
3. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residue in chicken excreta. The sample was extracted with acetonitrile, and purified with HLB solid phase extraction (SPE) cartridge. The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:At the spiked levers of 5.0,10 and 100μg/kg,the recoveries of decoquinate were 84.4%～100.1%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection of decoquinate was 2.5μg/kg and the limit of quantification was 5.0μg/kg.
4. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w., the study on pharmacokinetics of decoquinate in chicken plasma was conducted. The concentration-time data was fit to the two-compartment open model with the first order absorption. The t1/2ka, t1/2α, t1/2βand MRT(0-∞)were 2.614h,3.944h,19.334h and 47.065h respectively, and the Tmax and Cmax were 15h and 43.048 ng/mL respectively, which indicated that the absorption of decoquinate was slow and incomplete, and the elimination of decoquinate in plasma was also slow.
5. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w. , the elimination of decoquinate residue in chicken breast, leg, liver and kidney tissues were studied. After a withdrawal time of 1 day, the concentrations of decoquinate was the highest in chicken liver on day one(242μg/kg), the lowest in chicken breast (42μg/kg),but all much lower than the MRL (2000μg/kg) which manifested that the stipulation of withdrawal time of decoquinate in the chicken was right and scientific. The residue in chicken liver were all the highest among four chicken tissues after a withdrawal time of 1 to 5 day. Thereby liver was designated as the target tissue for monitoring decoquinate residue in chickens.
6. The study on elimination of decoquinate residue in chicken excreta was conducted. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w., the decoquinate residues at different withdrawal time in chicken excreta were studied. The concentration of decoquinate in chicken excreta was the highest on day one after administration (85.261mg/kg), and eliminate fast to 2.835mg/kg on day two. Within 1 day and 2 days, 65.6% and 75.9% of administrated dose were eliminated from excreta respectively, which showed that decoquinate has few absorption and excreted to the outside mainly via excreta.
7. The investigation of decoquinate residue in chicken in Fujian province was studied. Seventy chicken farms were selected randomly and the investigation was conducted, which showed that decoquinate was not use in most farms in Fujian province. Seventy-four chicken meat and liver samples were collected and tested. Decoquinate residues in all samples were below the corresponded LOQ, which indicated that decoquinate is still a new coccidiostat in our province, and has a potential appilcation prospective.
In conclusion, for the first time the methods of high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of decoquinate residues in chicken plasma, liver, meat, kidney and excreta were established and with these methods the studies on the pharmacokinetics and elimination of decoquinate in chicken were conducted, which submitted the theoretical data for the monitoring of decoquinate residue in chicken products, and give scientific guidance for the revising of the MRL and withdrawal time of decoquinate in chicken.
1、首次建立鸡血浆中癸氧喹酯的高效液相色谱-串联质谱测定方法。血浆样品经乙腈提取,氮气流吹干,采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,溶解残渣。采用电喷雾正离子电离模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在1 ng/mL～200 ng/mL范围内呈良好的线性关系,相关系数r~2均大于0.99;0.5、1、50 ng/mL 3个添加水平的回收率为85.0 %～96.9%,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为0.1 ng/mL,定量限为0.25 ng/mL。该方法简单快速、灵敏度高、选择性强,可用于鸡血浆中癸氧喹酯的药动学研究。
2、首次建立鸡肉、鸡肝和鸡肾组织中癸氧喹酯残留的高效液相色谱-串联质谱测定方法。样品经乙腈提取,正已烷脱脂,HLB固相萃取小柱净化;采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,电喷雾正离子电离模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在1.0、10、100μg/kg 3个添加水平的回收率均在75.5%～102.7%范围内,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为0.25μg/kg,定量限为0.5μg/kg。
3、首次建立鸡粪便中癸氧喹酯的高效液相色谱-串联质谱测定方法。样品经乙腈提取,HLB固相萃取小柱净化;采用0.1%甲酸乙腈溶液和0.1%甲酸水溶液为流动相,电喷雾正离子电离(ESI+)模式,多反应监测(MRM)检测模式,以内标法进行定量。结果表明:癸氧喹酯在5.0、10、100μg/kg 3个添加水平的回收率均在84.4%～100.1%范围内,批内、批间相对标准偏差(RSD)均小于15%,方法检出限为2.5μg/kg,定量限为5μg/kg。
4、癸氧喹酯在肉鸡体内的药动学研究。选用10只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡体内的药物动力学研究。肉鸡口服给药癸氧喹酯的血浆药时数据符合一级吸收二室开放模型,主要药动学参数:吸收半衰期为2.614h,分布半衰期为3.944h,消除半衰期为19.334h,达峰时间长达15h,达峰浓度较低,为43.048ng/mL,药物在血浆中的平均滞留时间为47.065h。结果表明肉鸡口服癸氧喹酯后吸收慢且不完全,但吸收进入血浆中的癸氧喹酯消除缓慢。
5、癸氧喹酯在肉鸡体内的残留消除规律研究。选用36只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡胸肌、腿肌、肝脏和肾脏组织中的残留消除规律研究。结果表明:停药1d,癸氧喹酯在肝脏中残留量最高,达242μg/kg,在胸肌中最低为42μg/kg,停药3d后癸氧喹酯均从不同组织中迅速消除,且残留量均小于300μg/kg,远低于农业部235号公告所规定的2000μg/kg最高残留限量要求,证明现行的休药期5d是合理的。停药后0～5d,肝脏中癸氧喹酯的残留量在几种常见组织中均最高,肝脏可作为动物源性食品中癸氧喹酯残留监控靶组织。
6、鸡粪中癸氧喹酯残留消除规律的研究。选用6只健康青脚麻鸡,按10mg/kg b.w.的剂量进行单次灌服癸氧喹酯在肉鸡粪便中的残留消除规律研究。结果表明:停药第1d癸氧喹酯的残留量就高达85.261 mg/kg,用药剂量的65.6%被排泄;停药2d后残留量迅速下降至2.835mg/kg,用药剂量的75.9%被排泄,表明癸氧喹酯在肉鸡体内吸收率低,生物利用度差,大部分药物未经吸收就直接通过粪便排出体外。粪便是癸氧喹酯在肉鸡体内的主要排泄途径。
7、福建省肉用鸡癸氧喹酯残留状况调查。分别随机选取了我省八地市70个肉鸡养殖场进行调查,共发放问卷70份,回收问卷70份,并按照随机原则在各设区、市市场遵照官方取样程序进行取样,共抽取了鸡肉样品和鸡肝样品各74份,并应用所建立的检测方法进行测定。结果表明:我省大部分养殖场从未使用过癸氧喹酯抗球虫药,抽检的148份鸡肉和鸡肝样品中也均未检出癸氧喹酯残留,表明癸氧喹酯在我省仍是一种有效的抗球虫药,具有很大的发展前景。
综上所述,本研究首次建立了鸡血浆、鸡肉、鸡肝、鸡肾及鸡粪中癸氧喹酯的高效液相色谱-串联质谱法,并阐明了鸡血浆中癸氧喹酯的药动学特征、鸡组织及鸡粪中癸氧喹酯的残留消除规律。研究结果不但为残留监控提供了重要的技术支撑,而且为我国修订癸氧喹酯残留限量标准和休药期提供了科学理论依据。
Decoquinate (6-ethyl-7-ethoxy-4-hydroxy-3-quinoline carboxylate) is a chemical quinolone coccidiostat as a in-feed prophylactic for broiler chickens to prevent and treat coccidiosis. Since it has not been widely used in China, few reports on decoquinate residue study in animal tissues were reported. In this research, the high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed for the determination of decoquinate residues in different chicken tissues and applied for the study on pharmacokinetics and residue elimination of decoquinate in chickens, which could provide technical support for the residue monitoring. The main results were as follows:
1. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residue in chicken plasma. The plasma sample was extracted with acetonitrile. The mobile phases consisted of 0.1% formic acid in acetonitrile and 0.1 % formic acid in water (78/22, v/v). The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:The calibration curve showed good linearity within the concentrations of 1 ng/mL～200 ng/mL with the correlation coefficient r~2>0.99. At the spiked levers of 0.5,1 and 50 ng/mL,the recoveries of decoquinate were 85.0%～96.9%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection (LOD) of decoquinate was 0.1 ng/mL and the limit of quantification (LOQ) was 0.25 ng/mL. The method was simple, sensitive and accurate which could be used for the pharmacokinetics study of decoquinate in chickens.
2. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residues in chicken meat, liver and kidney. The sample was extracted with acetonitrile, cleaned with hexane, and purified with HLB solid phase extraction (SPE) cartridge. The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:At the spiked levers of 1.0,10 and 100μg/kg,the recoveries of decoquinate were 75.5%～102.7%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection of decoquinate was 0.25μg/kg and the limit of quantification was 0.5μg/kg.
3. A new method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of decoquinate residue in chicken excreta. The sample was extracted with acetonitrile, and purified with HLB solid phase extraction (SPE) cartridge. The analyte was identified by positive electrospray ionization mode and multiple-reaction monitoring mode (MRM). The results showed as following:At the spiked levers of 5.0,10 and 100μg/kg,the recoveries of decoquinate were 84.4%～100.1%. The relative standard deviations (RSD) of intra- and inter-batch were both less than 15%.The limit of detection of decoquinate was 2.5μg/kg and the limit of quantification was 5.0μg/kg.
4. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w., the study on pharmacokinetics of decoquinate in chicken plasma was conducted. The concentration-time data was fit to the two-compartment open model with the first order absorption. The t1/2ka, t1/2α, t1/2βand MRT(0-∞)were 2.614h,3.944h,19.334h and 47.065h respectively, and the Tmax and Cmax were 15h and 43.048 ng/mL respectively, which indicated that the absorption of decoquinate was slow and incomplete, and the elimination of decoquinate in plasma was also slow.
5. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w. , the elimination of decoquinate residue in chicken breast, leg, liver and kidney tissues were studied. After a withdrawal time of 1 day, the concentrations of decoquinate was the highest in chicken liver on day one(242μg/kg), the lowest in chicken breast (42μg/kg),but all much lower than the MRL (2000μg/kg) which manifested that the stipulation of withdrawal time of decoquinate in the chicken was right and scientific. The residue in chicken liver were all the highest among four chicken tissues after a withdrawal time of 1 to 5 day. Thereby liver was designated as the target tissue for monitoring decoquinate residue in chickens.
6. The study on elimination of decoquinate residue in chicken excreta was conducted. After being orally administrated decoquinate with a single dose of 10 mg/kg b.w., the decoquinate residues at different withdrawal time in chicken excreta were studied. The concentration of decoquinate in chicken excreta was the highest on day one after administration (85.261mg/kg), and eliminate fast to 2.835mg/kg on day two. Within 1 day and 2 days, 65.6% and 75.9% of administrated dose were eliminated from excreta respectively, which showed that decoquinate has few absorption and excreted to the outside mainly via excreta.
7. The investigation of decoquinate residue in chicken in Fujian province was studied. Seventy chicken farms were selected randomly and the investigation was conducted, which showed that decoquinate was not use in most farms in Fujian province. Seventy-four chicken meat and liver samples were collected and tested. Decoquinate residues in all samples were below the corresponded LOQ, which indicated that decoquinate is still a new coccidiostat in our province, and has a potential appilcation prospective.
In conclusion, for the first time the methods of high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of decoquinate residues in chicken plasma, liver, meat, kidney and excreta were established and with these methods the studies on the pharmacokinetics and elimination of decoquinate in chicken were conducted, which submitted the theoretical data for the monitoring of decoquinate residue in chicken products, and give scientific guidance for the revising of the MRL and withdrawal time of decoquinate in chicken.
引文
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