J. vet. Pharmacol. Therap. 38, 383--391. doi: 10.1111/jvp.12195.
Comparative pharmacokinetics and tissue distribution of quinocetone in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) following the same experimental conditions Y. LIU* , † , ‡ , a X. AI
†,‡,a
F. WANG* H. YANG † N. XU † , ‡ & Q. YANG † , ‡ *Research Center for Trace Elements (Guangzhou), Huazhong Agricultural University, Guangzhou, China; †Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, China; ‡Hubei Freshwater Aquaculture Collaborative Innovation Center, Wuhan, China
Liu, Y., Ai, X., Wang F., Yang, H., Xu N., Yang Q. Comparative pharmacokinetics and tissue distribution of quinocetone in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) following the same experimental conditions. J. vet. Pharmacol. Therap. 38, 383– 391. The pharmacokinetics and tissue distribution of quinocetone (QCT) in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) were compared after oral administration of QCT (50 mg/kg body weight) at water temperature of 24 1 °C. Similar QCT plasma concentration–time profiles were found in the three species of cyprinid fish at the same dosage regimen and water temperature, which were all fitted two-compartment open pharmacokinetic model. However, different pharmacokinetic parameters were observed in crucian carp, common carp, and grass carp. The absorption rate constants (Ka) of QCT were 1.65, 1.40 and 1.74/h, respectively and absorption half-lives (t1/2ka) were 0.42, 0.49, and 0.40/h, respectively. The distribution half-life (t1/2a) was 2.83, 0.67, and 0.88 h, respectively, and elimination half-lives (t1/2b) of QCT were 133.97, 63.55, and 40.76 h, respectively. The maximum concentrations (Cmax) of QCT in plasma were 0.315, 0.182, and 0.139 lg/mL and the time to peak concentrations (Tp) were 1.45, 0.96, and 1.08 h, respectively. The area under the plasma concentration-time curves (AUC) were 12.35, 5.99, and 4.52 lgh/mL, respectively. The distribution volumes (Vd/F) of QCT were calculated as 117.81, 128.71, and 220.10 L/kg, respectively. The tissue analysis showed that a similar regularity was obtained in the three species of cyprinids with a single dose of 50 mg/kg body weight after oral administration at the same water temperature. The tissue concentration of QCT in each fish was in order of liver>kidney>muscle, while the residues of QCT in the three species of cyprinid fish were in order of crucian carp>common carp>grass carp. (Paper received 11 August 2014; accepted for publication 18 November 2014) Dr Yongtao Liu, Research Center for Trace Elements (Guangzhou), Huazhong Agricultural University, Guangzhou 510640, China. E-mails: thincat2005@sina. com; [email protected] a The authors contributed equally to this work.
INTRODUCTION Quinocetone, 3-methyl-2-quinoxalinbenzenevinylketo-1, 4dioxide, belonging to quinoxaline-1, 4-dioxide family, is independently developed by Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural © 2014 John Wiley & Sons Ltd
Sciences (Lanzhou, PR China). Its chemical structure is shown in Fig. 1. QCT was one kind of the national first-class new veterinary drugs and has been approved as an animal growth promoter in China since 2003 (Ministry of Agriculture, PR China, 2003). Because of its low toxicity and rapid elimination in animals (Wang et al., 2006; Zhang et al., 2007; Ban et al., 383
384 Y. Liu et al.
A and 61 mL of solution B was mixed, then the mixture solution was topped up to 400 mL with water. Solution A was prepared by dissolving 3.12 g of NaH2PO42H2O in 100 mL of water. Solution B was prepared by dissolving 7.17 g of Na2 HPO412H2O in 100 mL of water. Fig. 1. Chemical structure of QCT.
2010), QCT was widely used to improve production of animals such as swine, chicken, and fish in China (Wang et al., 1995; Xu et al., 1995; Carta et al., 2005; Wu et al., 2007; Chen et al., 2009; Li et al., 2010). So far, there have been some studies on the pharmacokinetic profiles and bioavailability of QCT in animals, such as swine (Li et al., 2002; Zhong et al., 2011; Wang et al., 2012), chicken (Li et al., 2002; Zhang et al., 2011), carp (Hu, 2008; Yang et al., 2010b), channel catfish (Yang et al., 2010b), and turbot (Li et al., 2011). As for QCT in swine, its main metabolites were identified (Shen et al., 2010; Wu et al., 2012), the pharmacokinetics of its major metabolites were also reported (Zhong et al., 2011; Wang et al., 2012). However, the main metabolites of QCT in fish, the pharmacokinetic and tissue distribution of QCT in crucian carp, common carp, and grass carp, and the similarities and differences of QCT disposition in crucian carp, common carp, and grass carp have not been reported. The objectives of the present study were to compare the pharmacokinetics and tissue distribution of QCT in crucian carp, common carp, and grass carp at 24 1 °C water after dosing the cyprinids with a single dose of 50 mg/kg body weight by oral administration. MATERIALS AND METHODS Chemicals QCT standard (purity ≥ 99.0%) and QCT technical powder (purity > 98.0%) were both collected from the Beijing Zhongnongfa Pharmaceutical CO, Ltd (Beijing, China). Acetonitrile, ethyl acetate, formic acid, and hexane were of HPLC grade and purchased from J. T. Baker (Deventer, Holland). The water used was prepared with a Milli-Q Gradient A10 water system (Millipore, Bedford, MA, USA). Anhydrous magnesium sulfate, Na2 HPO412H2O and NaH2PO42H2O were of analytical pure and purchased from Sinopharm Chemical Reagent Company (Shanghai, China). Primary secondary amine (PSA) sorbent was (40–60 lm) collected from Dikma Technologies Incorporated. (Lake Forest, CA, USA). QCT stock standard solution of 100 mg/L was prepared by dissolving QCT in acetonitrile and stored at 18 °C. The stability period of QCT stock solution lasts for 6 months. Intermediate solvent standard solution (1 mg/L) was prepared by diluting QCT stock solution with acetonitrile. 50 mM sodium phosphate buffer solution (pH 7.0) was prepared according to the following procedures: 39 mL of solution
Analytical methods Samples were analyzed using Surveyor Plus HPLC system (Surveyor MS pump plus and Surveyor autosampler plus, Thermo Scientific, San Jose, CA, USA) coupled with triple quadrupole tandem mass spectrometry (TSQ Quantum Access Max, Thermo Scientific). Data were acquired and processed through THERMO XCALIBUR 2.1 software (Thermo Scientific). HPLC conditions. QCT was separated on the Thermo BDS Hypersil C18 stainless steel column (150 mm 9 2.1 mm 9 5 lm). The column temperature was maintained at 30 °C. A gradient elution program was used with eluent A (acetonitrile containing 0.1% formic acid) and eluent B (water with 0.1% formic acid) at a flow rate of 0.2 mL/min. The elution started at 20% of eluent A for 1.0 min, then linearly increased up to 90% in 2 min, keeping constant for 3 min before being returned to the initial conditions in 0.1 min. The system was conditioned with 20% solvent A for 0.9 min. The total run time of a sample was 7.0 min. Injection volume was 20 lL. Mass conditions. The mass spectrometry was operated using heated electrospray ionization (HESI) in positive ion mode. Selected reaction monitoring (SRM) was performed on QCT protonated molecular ions using the parameters: spray voltage 3500 V, vaporizer temperature 300 °C, ion transport tube temperature 340 °C, sheath gas (high purity nitrogen) 35 arb, auxiliary gas (high purity nitrogen) 10 arb, Q1 peak width 0.70 amu, Q3 peak width 0.70 amu, collision gas (ultra-high purity argon) pressure 1.50 mTorr, san width 0.010, scan time 0.200 s. SRM for QCT was m/z 307.0 > 273.0 (Quantitative ion) with the collision energy of 18 ev, 307.0 > 131.0 and 307.0 > 143.0 (Qualitative ions) with the collision energy of 25 and 22 ev, respectively. Fish and experimental design Care and management of the fish were approved by the Institutional Fish Care and Use Committee of Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences. 110 healthy crucian carp (Carassius auratus, mean body weight 123.1 11.4 g), 110 healthy common carp (Cyprinus carpio L., mean body weight 137.4 14.6 g), and 110 healthy grass carp (Ctenopharyngodon idella, mean body weight 193.9 39.8 g) were provided by Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences (Wuhan, China). Each species of cyprinid fish was divided into two groups: the first group for pharmacokinetic research, the second group served as control. Fish were placed in fiberglass © 2014 John Wiley & Sons Ltd
388 Y. Liu et al. Table 2. The concentrations (ng/mL) of QCT in those three species of cyprinid fish plasma after single oral administration of 50 mg/kg body weight, respectively Time (h) 0.167 0.25 0.5 1 2 4 6 8 10 12 24 36 48 60 72 84 96 120 144 168 192
Crucian carp 30.30 137.65 138.56 409.07 260.09 265.39 126.17 156.85 82.57 76.99 45.69 49.60 44.03 46.18 44.57 33.04 31.76 ND ND ND ND
12.18 31.42 23.93 53.68 25.68 36.75 28.11 85.85 48.79 14.92 0.57 24.25 1.49 23.13 33.34 21.12 9.92
Commom carp 38.75 75.76 114.86 220.40 162.08 56.02 51.68 78.96 68.24 52.35 57.95 42.36 30.94 32.46 29.76 ND ND ND ND ND ND
10.65 22.67 32.52 46.89 34.57 18.95 20.63 18.46 20.28 10.27 11.85 8.76 12.56 5.70 6.84
Grass carp 50.98 122.17 103.51 214.67 116.53 109.62 99.70 82.35 70.80 49.37 48.26 45.46 34.07 30.94 18.57 ND ND ND ND ND ND
11.17 23.82 8.06 37.88 23.74 13.98 14.80 11.72 9.37 4.04 5.36 5.70 3.61 2.35 5.62
ND: not detected.
Fig. 3. Plasma concentration–time profiles of QCT in crucian carp ( ), common carp ( ) and grass carp ( ) following a single dose of 50 mg/kg body weight by oral administration.
employed the LLE and modified QuEChERS sample preparation procedures. A previous experiment on pharmacokinetics and tissue distribution of QCT in common carp (Cyprinus carpio L.) and channel catfish (Ictalurus punctatus) at the water temperature of 15 1 °C was also carried by our research group (Yang et al., 2010b). Hu (2008) reported that the pharmacokinetics and residue depletion of QCT in carp (Cyprinus carpio L.). The aim of our study was to reveal the comparative pharmacokinetic characteristics and tissue distribution rules of QCT in three species of cyprinid fish. The analysis of the data indicated that a two-compartment model best described QCT disposition in cru-
Table 3. Pharmacokinetic parameters for QCT in common carp (Cyprinus carpio L.), crucian carp (Carassius auratus) and grass carp (Ctenopharyngodon idella) after oral administration at a single dose of 50 mg/ kg body weight at the water temperature of 24 1 °C Parameters A a B b Ka tL Vd/F t1/2a t1/2b t1/2Ka K21 K10 K12 AUC CLb Tp Cmax
Unit
Crucian carp
Common carp
Grass carp
lg/mL h 1 lg/mL h 1 h 1 h L/kg h h h h 1 h 1 h 1 lgh/mL L/h/g h lg/mL
0.432 0.24 0.056 0.005 1.65 0.11 117.81 2.83 133.97 0.42 0.037 0.034 0.18 12.35 0.004048 1.45 0.315
1.266 1.042 0.062 0.011 1.40 0.096 128.71 0.67 63.55 0.49 0.18 0.064 0.81 5.99 0.0083 0.96 0.182
0.281 0.79 0.074 0.017 1.74 0.0011 220.10 0.88 40.76 0.40 0.27 0.050 0.48 4.52 0.011 1.08 0.139
A and B are zero time intercept of distribution phase and zero time intercept of elimination phase, respectively; a: distribution rate constant; b: elimination rate constant; Ka: absorption rate constant; tL: Lag time; Vd/F: the volume of distribution; t1/2a: distribution half-life; t1/2b: elimination half-life; t1/2ka absorption half-life; K12 and K21: first-order rate constants for drug distribution between the central and peripheral compartment; CLb: total body clearance; K10: elimination rate constant from the central compartment; Tp: the time point of maximum plasma concentration of the drug; Cmax: the maximum plasma concentration.
cian carp, common carp, and grass carp at the water temperature of 24 1 °C. The pharmacokinetics of the drug in channel catfish (Yang et al., 2010b) and turbot (Li et al., 2011) after oral administration at a single dose of 50 mg/kg body weight, and carp after intravenous injection at a single dose of 2.5 mg/kg body weight was also described by two-compartment model. However, Hu (2008) described the pharmacokinetics of QCT in carp after oral administration at a single dose of 200 mg/kg body weight by one-compartment open model. As previous studies refer to different temperatures, experimental schemes, sizes, and fish, it is difficult to conclude which is the factor affecting the best applicable type of model. We studied the pharmacokinetics and tissue distribution in three species of cyprinid fish at the same water temperature, in similar size and with the same experimental design, which is good for the comparison of disposition regularity of QCT in fish. In this study, the absorption rate constant (Ka) of QCT was in the order of grass carp>crucian carp>common carp at the same dosage regimen and water temperature, which was 1.74, 1.65, and 1.40/h, respectively. Li et al. (2011) reported that Ka of QCT in turbot was 1.296/h. The values of the apparent distribution volume (Vd/F) of QCT in crucian carp, common carp, and grass carp were 117.81, 128.71, and 220.10 L/kg, respectively, which indicated the main distribution in one tissue (Cao & Lu, 2005). The detecting data also showed that the © 2014 John Wiley & Sons Ltd
386 Y. Liu et al.
Pharmacokinetic parameters were calculated by the computer program 3P97 (version 1.0, edited by the Chinese Society of Mathematical Pharmacology, China) based on the assumption of first-order kinetics. The model was selected based on the residual sum of squares and the minimum Akaike’s information criterion (AIC) (Yamaoka & Nakagawa, 1978). The area under the concentration–time curve (AUC) was calculated using the trapezoidal rule and extrapolated to infinity (Ritschel, 1986). The volume of distribution (Vd/F), total body clearance (CLb), the elimination half-life (t1/2b), and distribution half-life (t1/2a) were calculated using the following equations, respectively: Vd/F = X0/(AUCb), CLb = bVd, t1/2b = 0.693/b, and t1/2a = 0.693/a (Ding et al., 2006).
the curve best fitting the absorption and distribution of elimination phases, a and b are the distribution and elimination rate constants, Ka is the absorption rate constant. The QCT plasma levels (C)-time course was described by the equation in Fig. 3. C = 0.432e 0.24(t 0.11) + 0.056e 0.005(t 0.11) 0.488e 1.65(t 0.11) for crucian carp, C = 1.266e 1.042(t 0.096) + 0.062e 0.011 (t 0.096) 1.328e 1.40(t 0.096) for common carp, and C = 0.79(t 0.0011) 0.281e + 0.074e 0.017(t 0.0011) 0.355e 1.74(t 0.0011) for grass carp. Pharmacokinetic parameters for QCT following oral administration of 50 mg/kg body weight in crucian carp, common carp, and grass carp at the water temperature of 24 1 °C are given in Table 3. The absorption rate constant (Ka) of QCT in crucian carp, common carp, and grass carp was 1.65, 1.40, and 1.74/h, respectively. The elimination half-life (t1/2b) of QCT was 133.97 h for crucian carp, 63.55 h for common carp, and 40.76 h for grass carp. The maximum plasma concentration of QCT (Cmax) and the time of reaching maximum plasma concentration (Tp) of QCT were 0.315 lg/mL for crucian carp at 1.45 h, 0.182 lg/mL for common carp at 0.96 h, and 0.139 lg/mL for grass carp at 1.08 h. The value of apparent volume of distribution was 117.81 L/kg in crucian carp, 128.71 L/kg in common carp, and 220.10 L/kg in grass carp. The area under the concentration–time curve (AUC) of QCT in crucian carp, common carp, and grass carp was 12.35, 5.99, and 4.52 lgh/mL. Total body clearance (CLb) was estimated to be 0.004048, 0.0083, and 0.011 L/h/g, respectively.
RESULTS
Tissue distribution
fied calibration curves for the plasma and tissues were built with QCT peak area of the selected quantification SRM transition of matrix-spiked solution versus the QCT concentration, which were used to study the linearity of QCT response and used for quantitative analysis. Recoveries were determined by comparing the peak areas of blank samples spiked before preparation with that of blank samples spiked after preparation. The precisions were examined by analyzing six replicates of different spiked matrices and expressed as the percentage relative standard deviation (%RSD). The limit of detection (LOD) of QCT was defined as the concentration of QCT resulting in a signalto-noise ratio (S/N) of 3. Pharmacokinetic and tissue distribution analysis
Method validation The use of analytical method described above, typical chromatograms of blank liver sample, liver sample of crucian carp spiked with standard QCT, and liver sample at h after oral administration are obtained and shown in Fig. 2. The retention time for QCT is approximately 5.35 min. Recovery, precision of interday and intraday, correlation index (r2) and LOD of the analytical method for QCT in the plasma and tissues of crucian carp, common carp, and grass carp are presented in Table 1. Recovery rates of QCT for plasma and tissues of the three species of cyprinids were from 74.85% to 86.31%. Intraday and interday precisions were common carp>grass carp.
ACKNOWLEDGEMENTS This present work was supported by the Special Fund for the Agroscientific Research in the Public Interest (No. 201203085), The financial provided by the Basic Scientific Research of Yangtze River Fisheries Research Institute (2013JBFM20) and the Basic Scientific Research of Chinese Academy of Fishery Sciences (2012A1005).
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Comparative pharmacokinetics and tissue distribution of quinocetone in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) following the same experimental conditions Y. LIU* , † , ‡ , a X. AI
†,‡,a
F. WANG* H. YANG † N. XU † , ‡ & Q. YANG † , ‡ *Research Center for Trace Elements (Guangzhou), Huazhong Agricultural University, Guangzhou, China; †Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, China; ‡Hubei Freshwater Aquaculture Collaborative Innovation Center, Wuhan, China
Liu, Y., Ai, X., Wang F., Yang, H., Xu N., Yang Q. Comparative pharmacokinetics and tissue distribution of quinocetone in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) following the same experimental conditions. J. vet. Pharmacol. Therap. 38, 383– 391. The pharmacokinetics and tissue distribution of quinocetone (QCT) in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) were compared after oral administration of QCT (50 mg/kg body weight) at water temperature of 24 1 °C. Similar QCT plasma concentration–time profiles were found in the three species of cyprinid fish at the same dosage regimen and water temperature, which were all fitted two-compartment open pharmacokinetic model. However, different pharmacokinetic parameters were observed in crucian carp, common carp, and grass carp. The absorption rate constants (Ka) of QCT were 1.65, 1.40 and 1.74/h, respectively and absorption half-lives (t1/2ka) were 0.42, 0.49, and 0.40/h, respectively. The distribution half-life (t1/2a) was 2.83, 0.67, and 0.88 h, respectively, and elimination half-lives (t1/2b) of QCT were 133.97, 63.55, and 40.76 h, respectively. The maximum concentrations (Cmax) of QCT in plasma were 0.315, 0.182, and 0.139 lg/mL and the time to peak concentrations (Tp) were 1.45, 0.96, and 1.08 h, respectively. The area under the plasma concentration-time curves (AUC) were 12.35, 5.99, and 4.52 lgh/mL, respectively. The distribution volumes (Vd/F) of QCT were calculated as 117.81, 128.71, and 220.10 L/kg, respectively. The tissue analysis showed that a similar regularity was obtained in the three species of cyprinids with a single dose of 50 mg/kg body weight after oral administration at the same water temperature. The tissue concentration of QCT in each fish was in order of liver>kidney>muscle, while the residues of QCT in the three species of cyprinid fish were in order of crucian carp>common carp>grass carp. (Paper received 11 August 2014; accepted for publication 18 November 2014) Dr Yongtao Liu, Research Center for Trace Elements (Guangzhou), Huazhong Agricultural University, Guangzhou 510640, China. E-mails: thincat2005@sina. com; [email protected] a The authors contributed equally to this work.
INTRODUCTION Quinocetone, 3-methyl-2-quinoxalinbenzenevinylketo-1, 4dioxide, belonging to quinoxaline-1, 4-dioxide family, is independently developed by Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural © 2014 John Wiley & Sons Ltd
Sciences (Lanzhou, PR China). Its chemical structure is shown in Fig. 1. QCT was one kind of the national first-class new veterinary drugs and has been approved as an animal growth promoter in China since 2003 (Ministry of Agriculture, PR China, 2003). Because of its low toxicity and rapid elimination in animals (Wang et al., 2006; Zhang et al., 2007; Ban et al., 383
384 Y. Liu et al.
A and 61 mL of solution B was mixed, then the mixture solution was topped up to 400 mL with water. Solution A was prepared by dissolving 3.12 g of NaH2PO42H2O in 100 mL of water. Solution B was prepared by dissolving 7.17 g of Na2 HPO412H2O in 100 mL of water. Fig. 1. Chemical structure of QCT.
2010), QCT was widely used to improve production of animals such as swine, chicken, and fish in China (Wang et al., 1995; Xu et al., 1995; Carta et al., 2005; Wu et al., 2007; Chen et al., 2009; Li et al., 2010). So far, there have been some studies on the pharmacokinetic profiles and bioavailability of QCT in animals, such as swine (Li et al., 2002; Zhong et al., 2011; Wang et al., 2012), chicken (Li et al., 2002; Zhang et al., 2011), carp (Hu, 2008; Yang et al., 2010b), channel catfish (Yang et al., 2010b), and turbot (Li et al., 2011). As for QCT in swine, its main metabolites were identified (Shen et al., 2010; Wu et al., 2012), the pharmacokinetics of its major metabolites were also reported (Zhong et al., 2011; Wang et al., 2012). However, the main metabolites of QCT in fish, the pharmacokinetic and tissue distribution of QCT in crucian carp, common carp, and grass carp, and the similarities and differences of QCT disposition in crucian carp, common carp, and grass carp have not been reported. The objectives of the present study were to compare the pharmacokinetics and tissue distribution of QCT in crucian carp, common carp, and grass carp at 24 1 °C water after dosing the cyprinids with a single dose of 50 mg/kg body weight by oral administration. MATERIALS AND METHODS Chemicals QCT standard (purity ≥ 99.0%) and QCT technical powder (purity > 98.0%) were both collected from the Beijing Zhongnongfa Pharmaceutical CO, Ltd (Beijing, China). Acetonitrile, ethyl acetate, formic acid, and hexane were of HPLC grade and purchased from J. T. Baker (Deventer, Holland). The water used was prepared with a Milli-Q Gradient A10 water system (Millipore, Bedford, MA, USA). Anhydrous magnesium sulfate, Na2 HPO412H2O and NaH2PO42H2O were of analytical pure and purchased from Sinopharm Chemical Reagent Company (Shanghai, China). Primary secondary amine (PSA) sorbent was (40–60 lm) collected from Dikma Technologies Incorporated. (Lake Forest, CA, USA). QCT stock standard solution of 100 mg/L was prepared by dissolving QCT in acetonitrile and stored at 18 °C. The stability period of QCT stock solution lasts for 6 months. Intermediate solvent standard solution (1 mg/L) was prepared by diluting QCT stock solution with acetonitrile. 50 mM sodium phosphate buffer solution (pH 7.0) was prepared according to the following procedures: 39 mL of solution
Analytical methods Samples were analyzed using Surveyor Plus HPLC system (Surveyor MS pump plus and Surveyor autosampler plus, Thermo Scientific, San Jose, CA, USA) coupled with triple quadrupole tandem mass spectrometry (TSQ Quantum Access Max, Thermo Scientific). Data were acquired and processed through THERMO XCALIBUR 2.1 software (Thermo Scientific). HPLC conditions. QCT was separated on the Thermo BDS Hypersil C18 stainless steel column (150 mm 9 2.1 mm 9 5 lm). The column temperature was maintained at 30 °C. A gradient elution program was used with eluent A (acetonitrile containing 0.1% formic acid) and eluent B (water with 0.1% formic acid) at a flow rate of 0.2 mL/min. The elution started at 20% of eluent A for 1.0 min, then linearly increased up to 90% in 2 min, keeping constant for 3 min before being returned to the initial conditions in 0.1 min. The system was conditioned with 20% solvent A for 0.9 min. The total run time of a sample was 7.0 min. Injection volume was 20 lL. Mass conditions. The mass spectrometry was operated using heated electrospray ionization (HESI) in positive ion mode. Selected reaction monitoring (SRM) was performed on QCT protonated molecular ions using the parameters: spray voltage 3500 V, vaporizer temperature 300 °C, ion transport tube temperature 340 °C, sheath gas (high purity nitrogen) 35 arb, auxiliary gas (high purity nitrogen) 10 arb, Q1 peak width 0.70 amu, Q3 peak width 0.70 amu, collision gas (ultra-high purity argon) pressure 1.50 mTorr, san width 0.010, scan time 0.200 s. SRM for QCT was m/z 307.0 > 273.0 (Quantitative ion) with the collision energy of 18 ev, 307.0 > 131.0 and 307.0 > 143.0 (Qualitative ions) with the collision energy of 25 and 22 ev, respectively. Fish and experimental design Care and management of the fish were approved by the Institutional Fish Care and Use Committee of Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences. 110 healthy crucian carp (Carassius auratus, mean body weight 123.1 11.4 g), 110 healthy common carp (Cyprinus carpio L., mean body weight 137.4 14.6 g), and 110 healthy grass carp (Ctenopharyngodon idella, mean body weight 193.9 39.8 g) were provided by Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences (Wuhan, China). Each species of cyprinid fish was divided into two groups: the first group for pharmacokinetic research, the second group served as control. Fish were placed in fiberglass © 2014 John Wiley & Sons Ltd
388 Y. Liu et al. Table 2. The concentrations (ng/mL) of QCT in those three species of cyprinid fish plasma after single oral administration of 50 mg/kg body weight, respectively Time (h) 0.167 0.25 0.5 1 2 4 6 8 10 12 24 36 48 60 72 84 96 120 144 168 192
Crucian carp 30.30 137.65 138.56 409.07 260.09 265.39 126.17 156.85 82.57 76.99 45.69 49.60 44.03 46.18 44.57 33.04 31.76 ND ND ND ND
12.18 31.42 23.93 53.68 25.68 36.75 28.11 85.85 48.79 14.92 0.57 24.25 1.49 23.13 33.34 21.12 9.92
Commom carp 38.75 75.76 114.86 220.40 162.08 56.02 51.68 78.96 68.24 52.35 57.95 42.36 30.94 32.46 29.76 ND ND ND ND ND ND
10.65 22.67 32.52 46.89 34.57 18.95 20.63 18.46 20.28 10.27 11.85 8.76 12.56 5.70 6.84
Grass carp 50.98 122.17 103.51 214.67 116.53 109.62 99.70 82.35 70.80 49.37 48.26 45.46 34.07 30.94 18.57 ND ND ND ND ND ND
11.17 23.82 8.06 37.88 23.74 13.98 14.80 11.72 9.37 4.04 5.36 5.70 3.61 2.35 5.62
ND: not detected.
Fig. 3. Plasma concentration–time profiles of QCT in crucian carp ( ), common carp ( ) and grass carp ( ) following a single dose of 50 mg/kg body weight by oral administration.
employed the LLE and modified QuEChERS sample preparation procedures. A previous experiment on pharmacokinetics and tissue distribution of QCT in common carp (Cyprinus carpio L.) and channel catfish (Ictalurus punctatus) at the water temperature of 15 1 °C was also carried by our research group (Yang et al., 2010b). Hu (2008) reported that the pharmacokinetics and residue depletion of QCT in carp (Cyprinus carpio L.). The aim of our study was to reveal the comparative pharmacokinetic characteristics and tissue distribution rules of QCT in three species of cyprinid fish. The analysis of the data indicated that a two-compartment model best described QCT disposition in cru-
Table 3. Pharmacokinetic parameters for QCT in common carp (Cyprinus carpio L.), crucian carp (Carassius auratus) and grass carp (Ctenopharyngodon idella) after oral administration at a single dose of 50 mg/ kg body weight at the water temperature of 24 1 °C Parameters A a B b Ka tL Vd/F t1/2a t1/2b t1/2Ka K21 K10 K12 AUC CLb Tp Cmax
Unit
Crucian carp
Common carp
Grass carp
lg/mL h 1 lg/mL h 1 h 1 h L/kg h h h h 1 h 1 h 1 lgh/mL L/h/g h lg/mL
0.432 0.24 0.056 0.005 1.65 0.11 117.81 2.83 133.97 0.42 0.037 0.034 0.18 12.35 0.004048 1.45 0.315
1.266 1.042 0.062 0.011 1.40 0.096 128.71 0.67 63.55 0.49 0.18 0.064 0.81 5.99 0.0083 0.96 0.182
0.281 0.79 0.074 0.017 1.74 0.0011 220.10 0.88 40.76 0.40 0.27 0.050 0.48 4.52 0.011 1.08 0.139
A and B are zero time intercept of distribution phase and zero time intercept of elimination phase, respectively; a: distribution rate constant; b: elimination rate constant; Ka: absorption rate constant; tL: Lag time; Vd/F: the volume of distribution; t1/2a: distribution half-life; t1/2b: elimination half-life; t1/2ka absorption half-life; K12 and K21: first-order rate constants for drug distribution between the central and peripheral compartment; CLb: total body clearance; K10: elimination rate constant from the central compartment; Tp: the time point of maximum plasma concentration of the drug; Cmax: the maximum plasma concentration.
cian carp, common carp, and grass carp at the water temperature of 24 1 °C. The pharmacokinetics of the drug in channel catfish (Yang et al., 2010b) and turbot (Li et al., 2011) after oral administration at a single dose of 50 mg/kg body weight, and carp after intravenous injection at a single dose of 2.5 mg/kg body weight was also described by two-compartment model. However, Hu (2008) described the pharmacokinetics of QCT in carp after oral administration at a single dose of 200 mg/kg body weight by one-compartment open model. As previous studies refer to different temperatures, experimental schemes, sizes, and fish, it is difficult to conclude which is the factor affecting the best applicable type of model. We studied the pharmacokinetics and tissue distribution in three species of cyprinid fish at the same water temperature, in similar size and with the same experimental design, which is good for the comparison of disposition regularity of QCT in fish. In this study, the absorption rate constant (Ka) of QCT was in the order of grass carp>crucian carp>common carp at the same dosage regimen and water temperature, which was 1.74, 1.65, and 1.40/h, respectively. Li et al. (2011) reported that Ka of QCT in turbot was 1.296/h. The values of the apparent distribution volume (Vd/F) of QCT in crucian carp, common carp, and grass carp were 117.81, 128.71, and 220.10 L/kg, respectively, which indicated the main distribution in one tissue (Cao & Lu, 2005). The detecting data also showed that the © 2014 John Wiley & Sons Ltd
386 Y. Liu et al.
Pharmacokinetic parameters were calculated by the computer program 3P97 (version 1.0, edited by the Chinese Society of Mathematical Pharmacology, China) based on the assumption of first-order kinetics. The model was selected based on the residual sum of squares and the minimum Akaike’s information criterion (AIC) (Yamaoka & Nakagawa, 1978). The area under the concentration–time curve (AUC) was calculated using the trapezoidal rule and extrapolated to infinity (Ritschel, 1986). The volume of distribution (Vd/F), total body clearance (CLb), the elimination half-life (t1/2b), and distribution half-life (t1/2a) were calculated using the following equations, respectively: Vd/F = X0/(AUCb), CLb = bVd, t1/2b = 0.693/b, and t1/2a = 0.693/a (Ding et al., 2006).
the curve best fitting the absorption and distribution of elimination phases, a and b are the distribution and elimination rate constants, Ka is the absorption rate constant. The QCT plasma levels (C)-time course was described by the equation in Fig. 3. C = 0.432e 0.24(t 0.11) + 0.056e 0.005(t 0.11) 0.488e 1.65(t 0.11) for crucian carp, C = 1.266e 1.042(t 0.096) + 0.062e 0.011 (t 0.096) 1.328e 1.40(t 0.096) for common carp, and C = 0.79(t 0.0011) 0.281e + 0.074e 0.017(t 0.0011) 0.355e 1.74(t 0.0011) for grass carp. Pharmacokinetic parameters for QCT following oral administration of 50 mg/kg body weight in crucian carp, common carp, and grass carp at the water temperature of 24 1 °C are given in Table 3. The absorption rate constant (Ka) of QCT in crucian carp, common carp, and grass carp was 1.65, 1.40, and 1.74/h, respectively. The elimination half-life (t1/2b) of QCT was 133.97 h for crucian carp, 63.55 h for common carp, and 40.76 h for grass carp. The maximum plasma concentration of QCT (Cmax) and the time of reaching maximum plasma concentration (Tp) of QCT were 0.315 lg/mL for crucian carp at 1.45 h, 0.182 lg/mL for common carp at 0.96 h, and 0.139 lg/mL for grass carp at 1.08 h. The value of apparent volume of distribution was 117.81 L/kg in crucian carp, 128.71 L/kg in common carp, and 220.10 L/kg in grass carp. The area under the concentration–time curve (AUC) of QCT in crucian carp, common carp, and grass carp was 12.35, 5.99, and 4.52 lgh/mL. Total body clearance (CLb) was estimated to be 0.004048, 0.0083, and 0.011 L/h/g, respectively.
RESULTS
Tissue distribution
fied calibration curves for the plasma and tissues were built with QCT peak area of the selected quantification SRM transition of matrix-spiked solution versus the QCT concentration, which were used to study the linearity of QCT response and used for quantitative analysis. Recoveries were determined by comparing the peak areas of blank samples spiked before preparation with that of blank samples spiked after preparation. The precisions were examined by analyzing six replicates of different spiked matrices and expressed as the percentage relative standard deviation (%RSD). The limit of detection (LOD) of QCT was defined as the concentration of QCT resulting in a signalto-noise ratio (S/N) of 3. Pharmacokinetic and tissue distribution analysis
Method validation The use of analytical method described above, typical chromatograms of blank liver sample, liver sample of crucian carp spiked with standard QCT, and liver sample at h after oral administration are obtained and shown in Fig. 2. The retention time for QCT is approximately 5.35 min. Recovery, precision of interday and intraday, correlation index (r2) and LOD of the analytical method for QCT in the plasma and tissues of crucian carp, common carp, and grass carp are presented in Table 1. Recovery rates of QCT for plasma and tissues of the three species of cyprinids were from 74.85% to 86.31%. Intraday and interday precisions were common carp>grass carp.
ACKNOWLEDGEMENTS This present work was supported by the Special Fund for the Agroscientific Research in the Public Interest (No. 201203085), The financial provided by the Basic Scientific Research of Yangtze River Fisheries Research Institute (2013JBFM20) and the Basic Scientific Research of Chinese Academy of Fishery Sciences (2012A1005).
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