喹赛多在鲤体内的药物动力学及残留的研究
摘要
以反相高效液相色谱(RP-HPLC)法为定性和定量手段，研究喹噁啉类新药喹赛多在鲤(Cyprinus carpio L.)体内的单剂量静脉注射和口灌给药后的药物动力学过程，以及药饲后组织中残留消除规律。静脉注射和口灌给药后，分别在0.08～48h内定时从鲤静脉采血，迅速分离血浆，于-20℃避光保存。血浆样品于测定前以甲醇去蛋白处理，取上清液作HPLC分析测定。实验数据处理采用Millemnium~(32)分析系统，选用ODS-C_(1(?))分析柱(150×4.6mm，5μm)，以甲醇∶水(15∶85／V∶V)为流动相，流速0.9mL／min，检测波长305nm。喹赛多(脱二氧喹赛多)对照品的最低检测限(LOD)0.005(0.01)μg／mL，最低可定量限(LOQ)0.01(0.02)μg／mL，浓度在0.01～1.0(0.02～2.0)μg／mL时与峰面积呈良好线性关系，线性方程为C=6×10~(-6)A-0.0019，r=0.9996(C=11.78×10~(-6)A+0.0119，r=0.9989)。血浆中喹赛多(脱二氧喹赛多)浓度在0.015、0.125、1.0μg／mL(0.03、0.25、2.0μg／mL)时，日内、日间变异系数分别＜5％(10％)和＜10％(15％)，平均回收率＞85％(80.0％)。静注给药后血药浓度-时间数据符合无吸收三室开放模型，药物动力学方程为C=11.4201e~(-8.0650t)+0.4926e~(-0.8327t)+0.0736e~(-0.0548t)。其主要药动学参数为：吸收速率常数(K_α)8.065h~(-1)，吸收半衰期(T_(1/2α))0.086h，中央室表观分布容积(V_c)166.86mL／kg wb；消除速率常数(K_β)0.8327h~(-1)，半衰期(T_(1/2β))0.832h；残留后相消除速率常数(K_γ)0.0548h~(-1)，药时曲线下面积(AUC)3.35(μg／mL)h。口灌给药后血药浓度-时间数据符合一级吸收一室开放模型，药物动力学方程为C=0.1371×(e~(-0.0823t)-e~(-0.3099t))。其主要药动学参数为：一级吸收速率常数(K_α)0.3099h~(-1)，吸收半衰期(T_((?)α))2.24h；一级消除速率常数(K_((?)))0.0823h~(-1)，消除半衰期(T_(1/2α))8.42h，表观清除率(CL_b)0.597L／h。药物在血液中达峰时间(T_((?)))5.83h，最大血药浓度(C_((?)))0.0623μg／mL。
以含喹赛多100mg／kg剂量，连续药饲投喂鲤12w，检测其在组织中的残留。于末次药饲投喂后0(当天)、2、4、5、6、8、10、15、20、25、30d随机取样五尾鱼，收集肝脏、肌肉和皮，-20℃避光保存。测定时，室温下解冻，每个样品以不同的方法预处理后进行分析测定：一份样品以常规方法预处理，经匀浆、提取、脱脂后作HPLC检测；另一份样品以碱水解、SPE柱净化后再作HPLC检测。常规方法预处理样品，同时测定喹赛多、喹噁啉-2-羧酸、脱二氧喹赛多三种化合物。碱水解方法预处理样品，测定喹噁啉-2-羧酸，该处理可将结合及游离态的喹噁啉-2-羧
哇赛多在鲤体内的药物动力学及残留的研究
酸全部从组织中释放出来，并作为靶代谢物进行检测，以了解鲤的肌肉、皮以及肝
脏组织中药物残留情况，并据此定出休药期。常规方法预处理中哇赛多、哇嚷琳一2-
梭酸、脱二氧喳赛多三种化合物的最低检测限分别为0.005、0.01、0.01陀/g，最
低可信定量限0.01、0.02、0.02陀/g，日内、日间变异系数分别<10%和<15%
(n=5)，回收率在70~90%之间。肌肉中喳嗯琳一2一梭酸的含量最高，消除最慢。水
解预处理方法中喳嗯琳一2一梭酸在鲤组织中的最低检测限为0.01件g/g，最低可信定
量限0.02陀/g。组织中喳嗯琳一2一梭酸的平均回收率为81.8士2.1%，日内及日间
变异系数分别<5%和<10%(n=5)。
实验结果显示:哇赛多在鲤体内的药物动力学及残留的研究方法准确、可靠。
哇赛多在鲤体内具有分布迅速、广泛，而消除缓慢的药物动力学特点。与哺乳动物
相比具有较长的消除半衰期，但是生物利用度较低，仅有1.3%。残留消除实验中，
肝脏中喳嗯琳一2一梭酸含量最高，消除最慢，因而可以认为肝脏为残留消除的靶组
织，喳嗯琳一2一梭酸为靶化合物并存在体内的结合。喳嚷琳一2一梭酸在第巧d仍有检
出，但己低于0.03陀/g。
根据美国食品与药品管理局(阳A)的最新标准:喳唔琳一2一梭酸的残留限量
(MRLs)为0.3件g/g，鲤药饲喂养12w后停药当天(5h)哇嘻琳一2一梭酸的浓度
值就仅为0.14士0.04陀/g，那么可以确定喳赛多在鲤体内为零休药期。
The pharmacokinetics and residue depletion of cyadox were studied in carp (Cyprinus carpio L.). Cyadox levels were determined in plasma after single intravenous (2 mg/kg bw) and oral (40 mg/kg bw) administration. The residue depletion levels of cyadox and its main metabolite (the 100 mg/kg feed additives level, the treatment period for 12w) in the several tissues were also observed in this paper. Plasma samples were collected from tail-vein at every different interval after two administration. Cyadox and desoxycyadox in the plasma was extracted and de-proteined by methanol. The contents were determined by reversed-phase high performance liquid chromatography (HPLC). The chromatography separation of the plasma samples were achievd on Hypersil-C18 column (5 μm, 150×4.6 mm) with Millemnium32 HPLC instrument using a degassed mixture methanol: water(15: 85/v: v) as the mobile phase, the flow-rate is 0.9 mL/min, the wavelength is 305 nm. The limit of detection(LOD) and the limit of quanthatio
n(LOQ) of the cyadox a
nd desoxycyadox standard solution is respectively 0.005μg/mL, 0.01 μg/mL and 0.01μg/mL. 0.02μg/mL. The standard calibration curve of drugs solution were linear in the range of 0.01-1.0ng/mL. The linear equation of cyadox and deosxycyadox were respectively C=6.0×10-6A-0.0019(r=0.9996) and C=11.78×10-6A+0.0119 (r=0.9989). When the plasma concentration of cyadox was at 0.015, 0.125. 1.0μg/mL, the intra-day and inter-day coefficient of variance was respectively less than 5% and 10%, the average recovery was over 85.9%. Whereas, the plasma concentration of desoxycyadox was at 0.03, 0.25. 2.0 μg/mL, the intra-day and niter-day coefficient of variance was respectively less than 10% and 15%, the average recovery was over 79.2%. The single dose intravemous and oral administrations concentration-time data were analyzed by pharmacokinetic compartment analysis soft (PKANALYST). The procession of cyadox after intravenous administration was fit the three-compartment open model pharmacoki
ne
tic equation:
C=11.4201e-8.0650t+0.4926e-0.327t + 0.0736V0.0548t. The main pharmacokinetic parameters of cyadox in carp were as follows: AUC 3 .3503 μg h/mL, Vc 166.8574 mL/kg wb, CL 11.9393L/h,T1/2a. 0.086 h,T1/2beta 0.832 h.T1/2gamma, 12.64 h. The procession of cyadox after oral administration was fit the one-compartment open model, pharmacokinetic equaion:
C=0.1371×(e-0.0823t-e-0.3099t). The main pharmacokinetic parameters of cyadox in carp were as follows: Cmax was 0.0623 ug/mL at 5.83 h post-injection. The Vj area was 7.2506 mL/kgbw.
Moreover, according to the pharmacokinetics results, the feed additives was supplied and given the same diet supplemented with 100 mg kg-1 levels cyadox, the treatment period with feed additives 12 w consecutive days. Then, the tissue samples (muscle, skin and liver; 5 animals/time-point) were collected at every different interval (0, 2, 4, 5, 6, 8, 10, 15, 20, 25, 30 d) after administration. The samples were stored at-20℃ until analysis. When determination, the samples were dissolved under physical temperature and were used to analysis with two routes: one part-samples was treated with regular (method 1); other part-samples was dealed with hydrolysis (method 2). On the method 1, cyadox, desoxycyadox, QCA (floating) of the samples was detected simultaneously in one HPLC system. On the method 2, we considered the tissues occured to the bounding residue, therefore, the operation acted with hydrolysis method. By this method, the bounding and floating status of QCA were all released and detected as the final ta
r
get metabolite. According to the condition, we can gain the drug withdrawal period. In method 1, the LOD and LOQ of cyadox, desoxycyadox, QCA (floating) were respectively 0.005, 0.01, 0.01μg/mL and 0.01, 0.02, 0.02μg/mL. The average recovery was over 69.2 ~ 86.3 % at the concentration lever of 0.02, 0.04, 0.08, 0.16 ug/mL and the intra-day and inter-day coefficient of variance were respectively less than 10 % and 15
以含喹赛多100mg／kg剂量，连续药饲投喂鲤12w，检测其在组织中的残留。于末次药饲投喂后0(当天)、2、4、5、6、8、10、15、20、25、30d随机取样五尾鱼，收集肝脏、肌肉和皮，-20℃避光保存。测定时，室温下解冻，每个样品以不同的方法预处理后进行分析测定：一份样品以常规方法预处理，经匀浆、提取、脱脂后作HPLC检测；另一份样品以碱水解、SPE柱净化后再作HPLC检测。常规方法预处理样品，同时测定喹赛多、喹噁啉-2-羧酸、脱二氧喹赛多三种化合物。碱水解方法预处理样品，测定喹噁啉-2-羧酸，该处理可将结合及游离态的喹噁啉-2-羧
哇赛多在鲤体内的药物动力学及残留的研究
酸全部从组织中释放出来，并作为靶代谢物进行检测，以了解鲤的肌肉、皮以及肝
脏组织中药物残留情况，并据此定出休药期。常规方法预处理中哇赛多、哇嚷琳一2-
梭酸、脱二氧喳赛多三种化合物的最低检测限分别为0.005、0.01、0.01陀/g，最
低可信定量限0.01、0.02、0.02陀/g，日内、日间变异系数分别<10%和<15%
(n=5)，回收率在70~90%之间。肌肉中喳嗯琳一2一梭酸的含量最高，消除最慢。水
解预处理方法中喳嗯琳一2一梭酸在鲤组织中的最低检测限为0.01件g/g，最低可信定
量限0.02陀/g。组织中喳嗯琳一2一梭酸的平均回收率为81.8士2.1%，日内及日间
变异系数分别<5%和<10%(n=5)。
实验结果显示:哇赛多在鲤体内的药物动力学及残留的研究方法准确、可靠。
哇赛多在鲤体内具有分布迅速、广泛，而消除缓慢的药物动力学特点。与哺乳动物
相比具有较长的消除半衰期，但是生物利用度较低，仅有1.3%。残留消除实验中，
肝脏中喳嗯琳一2一梭酸含量最高，消除最慢，因而可以认为肝脏为残留消除的靶组
织，喳嗯琳一2一梭酸为靶化合物并存在体内的结合。喳嚷琳一2一梭酸在第巧d仍有检
出，但己低于0.03陀/g。
根据美国食品与药品管理局(阳A)的最新标准:喳唔琳一2一梭酸的残留限量
(MRLs)为0.3件g/g，鲤药饲喂养12w后停药当天(5h)哇嘻琳一2一梭酸的浓度
值就仅为0.14士0.04陀/g，那么可以确定喳赛多在鲤体内为零休药期。
The pharmacokinetics and residue depletion of cyadox were studied in carp (Cyprinus carpio L.). Cyadox levels were determined in plasma after single intravenous (2 mg/kg bw) and oral (40 mg/kg bw) administration. The residue depletion levels of cyadox and its main metabolite (the 100 mg/kg feed additives level, the treatment period for 12w) in the several tissues were also observed in this paper. Plasma samples were collected from tail-vein at every different interval after two administration. Cyadox and desoxycyadox in the plasma was extracted and de-proteined by methanol. The contents were determined by reversed-phase high performance liquid chromatography (HPLC). The chromatography separation of the plasma samples were achievd on Hypersil-C18 column (5 μm, 150×4.6 mm) with Millemnium32 HPLC instrument using a degassed mixture methanol: water(15: 85/v: v) as the mobile phase, the flow-rate is 0.9 mL/min, the wavelength is 305 nm. The limit of detection(LOD) and the limit of quanthatio
n(LOQ) of the cyadox a
nd desoxycyadox standard solution is respectively 0.005μg/mL, 0.01 μg/mL and 0.01μg/mL. 0.02μg/mL. The standard calibration curve of drugs solution were linear in the range of 0.01-1.0ng/mL. The linear equation of cyadox and deosxycyadox were respectively C=6.0×10-6A-0.0019(r=0.9996) and C=11.78×10-6A+0.0119 (r=0.9989). When the plasma concentration of cyadox was at 0.015, 0.125. 1.0μg/mL, the intra-day and inter-day coefficient of variance was respectively less than 5% and 10%, the average recovery was over 85.9%. Whereas, the plasma concentration of desoxycyadox was at 0.03, 0.25. 2.0 μg/mL, the intra-day and niter-day coefficient of variance was respectively less than 10% and 15%, the average recovery was over 79.2%. The single dose intravemous and oral administrations concentration-time data were analyzed by pharmacokinetic compartment analysis soft (PKANALYST). The procession of cyadox after intravenous administration was fit the three-compartment open model pharmacoki
ne
tic equation:
C=11.4201e-8.0650t+0.4926e-0.327t + 0.0736V0.0548t. The main pharmacokinetic parameters of cyadox in carp were as follows: AUC 3 .3503 μg h/mL, Vc 166.8574 mL/kg wb, CL 11.9393L/h,T1/2a. 0.086 h,T1/2beta 0.832 h.T1/2gamma, 12.64 h. The procession of cyadox after oral administration was fit the one-compartment open model, pharmacokinetic equaion:
C=0.1371×(e-0.0823t-e-0.3099t). The main pharmacokinetic parameters of cyadox in carp were as follows: Cmax was 0.0623 ug/mL at 5.83 h post-injection. The Vj area was 7.2506 mL/kgbw.
Moreover, according to the pharmacokinetics results, the feed additives was supplied and given the same diet supplemented with 100 mg kg-1 levels cyadox, the treatment period with feed additives 12 w consecutive days. Then, the tissue samples (muscle, skin and liver; 5 animals/time-point) were collected at every different interval (0, 2, 4, 5, 6, 8, 10, 15, 20, 25, 30 d) after administration. The samples were stored at-20℃ until analysis. When determination, the samples were dissolved under physical temperature and were used to analysis with two routes: one part-samples was treated with regular (method 1); other part-samples was dealed with hydrolysis (method 2). On the method 1, cyadox, desoxycyadox, QCA (floating) of the samples was detected simultaneously in one HPLC system. On the method 2, we considered the tissues occured to the bounding residue, therefore, the operation acted with hydrolysis method. By this method, the bounding and floating status of QCA were all released and detected as the final ta
r
get metabolite. According to the condition, we can gain the drug withdrawal period. In method 1, the LOD and LOQ of cyadox, desoxycyadox, QCA (floating) were respectively 0.005, 0.01, 0.01μg/mL and 0.01, 0.02, 0.02μg/mL. The average recovery was over 69.2 ~ 86.3 % at the concentration lever of 0.02, 0.04, 0.08, 0.16 ug/mL and the intra-day and inter-day coefficient of variance were respectively less than 10 % and 15
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