Pharmacokinetics of Florfenicol in Crucian Carp (Carassius Auratus Cuvieri) After a Single Intramuscular Or Oral Administration
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J. vet. Pharmacol. Therap. 34, 460–463. doi: 10.1111/j.1365-2885.2011.01273.x. Pharmacokinetics of florfenicol in crucian carp (Carassius auratus cuvieri) after a single intramuscular or oral administration H.-Y. ZHAO*,1 Zhao, H.-Y., Zhang, G.-H., Bai, L., Zhu, S., Shan, Q., Zeng, D.-P., Sun Y.-X. G.-H. ZHANG ,1 Pharmacokinetics of florfenicol in crucian carp (Carassius auratus cuvieri) after a single intramuscular or oral administration. J. vet. Pharmacol. Therap. 34, L. BAI* 460–463. S. ZHU* Q. SHAN* The pharmacokinetics of florfenicol (FF) was studied in plasma after a single D.-P. ZENG* & dose (40 mg ⁄ kg) of intramuscular (i.m.) or oral gavage (p.o.) administration to crucian carp (Carassius auratus cuvieri) in freshwater at 25 °C. Ten fish per Y.-X. SUN* sampling point were examined after treatment. The data were fitted to two- *Laboratory of Veterinary Pharmacology, compartment open models follow both routes of administration. The estimates College of Veterinary Medicine, South China of total body clearance (CLb), volume of distribution (Vd ⁄ F), and absorption Agricultural University, Guangzhou, China; half-life (T1 ⁄ 2(ka)) were 0.067 L ⁄ h ⁄ kg and 0.145 L ⁄ h ⁄ kg, 2.21 L ⁄ kg and College of Animal Science and Veterinary 1.04 L ⁄ kg, 2.75 and 1.54 ⁄ h following i.m. and p.o. administration, respec- Medicine, Henan Agricultural University, tively. After i.m. injection, the elimination half-life (T1 ⁄ 2(b)) was calculated to be Zhengzhou, China 38.2h, the maximum plasma concentration (Cmax) to be 16.82 lg ⁄ mL, the time to peak plasma FF concentration (Tmax) to be 1.50 h, and the area under the plasma concentration–time curve (AUC) to be 597.4 lg ⁄ mLÆh. Following p.o. administration, the corresponding estimates were 2.17 h, 29.32 lg ⁄ mL, 1.61 h, and 276.1 lg ⁄ mLÆh. (Paper received 23 September 2010; accepted for publication 16 December 2010) Yong-Xue Sun, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510640, China. Tel.: +862085280237; Fax: +862085284896; E-mail: [email protected] 1Zhao and Zhang are both the first author. INTRODUCTION The pharmacokinetics of FF has been reported in Atlantic salmon (Martinsen et al., 1993; Horsberg et al., 1994, 1996), red Crucian carp are one kind of the most economically important pacu (Lewbart et al., 2005), tilapia (Feng et al., 2008; Feng & Jia., freshwater fishes in China and have become a consumer and 2009), cod (Hansen & Horsberg, 2000; Samuelsen et al., 2003), farmers’ favorite for its nutritional value, taste, strong adapt- koi carp, and three spot gourami (Yanong & Curtis., 2005), Korean ability, and efficient growth. Bacterial disease resulted in huge catfish (Park et al., 2006) and sharks (Zimmerman et al., 2006). aquacultural losses in 2009, and the authors feel that anti- The results showed that FF was absorbed rapidly, distributed microbial therapy is essential to reduce morbidity and mortality extensively, and eliminated slowly. Nevertheless, information in the future. Data derived from pharmacokinetic investigations about the pharmacokinetics of FF in crucian carp is deficient. The in crucian carp are important for establishing correct dosage aim of this study was to determine the pharmacokinetics of FF in regimes, promoting optimal use of the drug in question, and healthy crucian carp at 25 °C following a single i.m. or p.o. dose. minimizing environmental impact. Florfenicol (FF) is a broad-spectrum chloromycetin series antibiotics that works by inhibiting bacterial protein synthesis at MATERIALS AND METHODS the ribosome (Cannon et al., 1990; Papich & Riviere, 2001). FF is at the moment the second most used antibacterial agent in Chemicals Norwegian aquaculture (Samuelsen et al., 2003). FF has become the principal drug for treating furunculosis in of ranidae fish, FF (99.4% assay purity) and chloramphenicol (CP) (99.7%) as the bacterial cold water disease, rainbow trout fry syndrome, and analytical standard were purchased from the National Institute for enteric septicemia of catfish in Europe and North America. the Control of Pharmaceutical and Biological Products, 460 Ó 2011 Blackwell Publishing Ltd Pharmacokinetics of florfenicol in crucian carp 461 P.R. China. FF with a chemical purity of 98% was donated by combined ethyl acetate extract was evaporated to dryness in Heng-Feng-Qiang (Shanghai, China). HPLC-grade acetonitrile 40 °C water bath pot under a gentle stream of nitrogen and and methanol were purchased from Merck, German, while all the reconstituted with 1 mL of mobile phase, 20 lL volume of which other chemicals were of analytical grade and made in China. was injected into HPLC system. Animals Pharmacokinetic analysis Clinically healthy crucian carp, weighing 260 ± 30 g, bought The pharmacokinetic analysis of FF was performed using Win- from one aquaculture plant in Guangdong province, were reared Nonlin4.01 (Pharsight Corporation, Mountain View, CA, USA). in a pond (20 m3), supplied with circulating water and oxygen Following a single dose of i.m. and p.o. administration, the continuously by an inflation pump. Heat rods were used to plasma concentration–time data were both fitted to two- maintain the water temperature at 25 ± 1 °C. The fish were compartment open models with first-order rate processes best allowed to acclimate for three days, fed a drug-free commercial and could be described by the equation: C = Le)at + diet. The fish had no previous exposure to any antibiotic, and no Me)bt ) (L + M)e)Kat. a is the distribution rate constant, b is the drugs were given to the animals during the acclimation or study elimination rate constant, and Ka is the absorption rate constant. periods. To rule out the influence of food content on the Parameters calculated i.m. and p.o. were area under the plasma absorption of FF, the fish were starved each for 24 h before and concentration–time curve (AUC) was calculated from after drug administration. AUC = A ⁄ a + B ⁄ b ) (A + B) ⁄ Ka; the volume of distribution (Vd ⁄ F) was calculated from Vd ⁄ F =X0 ⁄ (AUCb)(X0 is initial dose); and the total body clearance (CL ) was calculated from CL = bV . Experimental designs b b d The fish were divided into two groups for i.m. and p.o. administrations, respectively. The FF solution for i.m. RESULTS (40 mg ⁄ mL) and p.o. (5 mg ⁄ mL) was prepared by dissolving the pure FF powder in a minute quantity of dimethylformamide A linear relationship existed in the calibration curve over the and mixed with water final. Individual fish was injected with FF range of 0.03–16 lg ⁄ mL, which always yielded a correlation solution at the right epaxial of the third vertebrae (i.m.) or coefficient exceeding 0.997. The precision and accuracy for FF drenched with FF solution with gavage needle (p.o.) at the dose of were 3.86–5.41% and 91.25–98.37%, respectively. 40 mg ⁄ kg (b.w.). The blood samples were taken from tail sinus of Plasma concentration of FF vs. time curves and the pharma- ten fish at 0.25, 0.5, 1, 3, 6, 9, 12, 18, 24, 48, 72, 120 h, and cokinetic parameters for FF following i.m. and p.o. administra- 168 h after i.m. and p.o treatment, respectively. All samples were tion of a single dose at 40 mg ⁄ kg b.w. were shown in Fig. 1 and immediately frozen and stored at )20 °C until analysis. Table 2, respectively. After i.m. injection and p.o. administration, the fat of FF in crician carp could be determined by the equations: Analytical method C = 9.77 e)0.076t + 8.63 e)0.018t ) 18.4 e)2.75t and C = 41.12 The chromatographic method was performed briefly as described e)0.178t + 2.17 e)0.03t ) 43.29 e)1.54t, respectively. The calcu- by Vue et al. (2002). CP was used as an internal standard in the lated maximum plasma concentration (Cmax) values (16.82 and analytical method. The mobile phase consisted of a mixture of 29.32 lg ⁄ mL) were reached at 1.50 and 1.61 h following i.m. acetonitrile–water at a ratio of 20:80 (v ⁄ v) and adjusted to pH of and p.o. administration, and the estimates of AUC were 597.37 7.8 with phosphate buffer. The injection volume was 20 lL, (lg ⁄ ml)Æh and 276.12 (lg ⁄ ml)Æh. The absorption half-life monitoring wavelength was at 223 nm, oven temperature was (T1 ⁄ 2ka) and elimination half-life (T1 ⁄ 2b) of FF were 0.25 and at 30 °C, and the flow rate was 1 mL ⁄ min. Calibration curve was prepared in the range of 0.0316 lg ⁄ mL. CP (internal 35 standard) was added to spike samples 20 lL at 500 lg ⁄ mL 30 concentration. 25 i.m. g/mL) p.o. μ 20 Sample preparation 15 The extraction procedure was carried out according to the 10 procedure of Feng et al. (2008). Concentration ( Blood samples (1 mL) were placed in a 15-mL plastic 5 centrifuge tube and spiked with 20 lL of internal standard 0 0 24 48 72 96 120 144 168 (CP, 500 lg ⁄ mL). Ethyl acetate(3 mL), as an extractant, was Time (h) added, and the mixture was mechanically shacked and centri- fuged for 12 min at 1680 g. The supernatant was transferred to Fig. 1. Florfencol levels (mean ± SD, n = 10) in plasma of crucian carp 12-mL glass tubes. The extraction step was repeated. The after a single 40 mg ⁄ kg i.m. or p.o. dose. Ó 2011 Blackwell Publishing Ltd 462 H.-Y.