(08) 김풍호.hwp

Kor J Fish Aquat Sci 43(6), 623-628 한수지, 43(6), 623-628, 2010 양식잉어및뱀장어에경구투여한 fluroquinolone 계항생제의체내잔류량의변화 조미라 박큰바위 이희정 김지회 1 이태식 2 정승희 3 이두석 4 윤호동 4 김풍호 4 국립수산과학원남서해수산연구소, 1 남동해수산연구소, 2 서해수산연구소, 3 전략양식연구소, 4 식품안전과 Distribution of Fluoroquinolones in the Carp (Cyprinus carpio) and Eel (Anguilla japonica) following their Oral Administration Mi Ra Jo, Kunbawui Park, Hee Jung Lee, Ji Hoe Kim 1, Tae Seek Lee 2, Sung Hee Jung 3, Doo Seog Lee 4, Ho Dong Yoon 4 and Poong Ho Kim 4 * Southwest Sea Fisheries Research Institute, NFRDI, Yeosu 556-823, Korea 1 Southeast Sea Fisheries Research Institute, NFRDI, Tongyeong 650-943, Korea 2 West Sea Fisheries Research Institute, NFRDI, Incheon 400-420, Korea 3 Aquaculture Research Institute, NFRDI, Busan 619-705, Korea 4 Food Safety Research Division, NFRDI, Busan 619-705, Korea The distribution of fluoroquinolones was investigated in the carp (Cyprinus carpio) and eel (Anguilla japonica) after an oral dose of 20 mg/kg body weight/day for 35 days. Blood samples were collected at 5 and 10 hours and 1, 2, 3, 5, 7, 9, 13, 20, 30, and 35 days after treatment. The fluoroquinolone concentrations were determined high- performance liquid chromatography with an ultraviolet detector. The recovery rates of fluoroquinolones in the fish samples ranged from 91.4-96.6, 91.2-96.5, and 90.4-98.6% for concentrations of 0.1, 0.5, and 1.0 μg/g, respectively. In the blood of carp, ciprofloxacin, enrofloxacin, norfloxacin, and sarafloxacin reached maximums level of 11.03, 9.37, 9.10, and 9.81 μg/g 10 hours, 1 day, 10 hours, and 10 hours after treatment, respectively. In the eel blood, these reached maximum levels of 12.65, 11.18, 11.91, and 8.74 μg/g all at 10 hours. Carp sample concentrations of ciprofloxacin, enrofloxacin, norfloxacin, and sarafloxacin were not measurable 20, 30, 20, and 20 days after treatment, respectively, in all experiments (<LOQ; limit of quantitation). Eel sample concentrations of ciprofloxacin, enrofloxacin, norfloxacin, and sarafloxacin were not measurable 20, 35, 30, and 20 days after treatment, respectively, in all experiments (<LOQ). Key words: Fluoroquinolones, Oral administration, Carp, Eel, HPLC 서론 Fluoroquinolone계열항생제는 DAN gyrase (topoisomerase II) 및 topoisomerase IV 작용을억제하여 DNA 합성을저해됨으로서항균작용을나타내며, 그램음성균뿐만아니라그램양성균, Mycoplasma 속등에이르기까지광범위한항균작용을나타내고체내흡수가빠른장점을가지고있어서사람이나동물의세균성질병치료에많이사용되어왔다 (Chevalier et al., 1981; Kasuga et al., 1984). 우리나라어류양식산업에도 1980년대초에 fluoroquinolone 계항생제를처음도입한이후그사용량이점차증가하게되었고, 어류질병치료에중요한항생물질로대두되었다. 또한 fluoroquinolone계항생제의경우기존의 quinolone계열보다어류의질병치료에매우효과적이며, 각종세균에대한최소발육억제농도도기존 quinolone계열보다뛰어난감수성을나타내었다 (Markwardt and Klontz, 1982; Heo et al., 1992; Corresponding author: phkim@nfrdi.go.kr Treves-Brown, 2000). 그러나최근들어 quinolone 계항생제내성 Salmonella 속균및 Campylobacter 속균이검출되는등축산물내항생제의잔류로인하여약제내성, 안전성및유효성에문제가되어미국, EU, 일본등에서규제를강화하고있다 (Herikstad et al., 1997; Smith et al., 1999). 이에우리나라도동물용의약품으로판매되었던 fluoroquinolone 계항생제에대하여 2008 년 7 월 1 일부터약사법제 76 조및 85 조에의거하여국내제조및수입금지조치되어제품으로판매가금지되었고, 식품의약품안전청에서도어류및갑각류에대하여잔류허용기준치를 enrofloxacin 와 ciprofloxacin 합계로 0.1 mg/kg 과 ofloxacin, pefloxacin, norfloxacin 을수산물에대하여불검출로지정되어관리하고있다 ( 식품의약품안전청고시 2008-51 호 ). 이는 fluoroquinolone 계항생제가 2008 년 7 월 1 일이전까지판매된제품에한하여유효기간까지사용할수있기때문에현재사용되고있는 fluoroquinolone 계항생제에대하여지속적으로관리를해야할필요성이있다. 따라서 623

624 조미라 박큰바위 이희정 김지회 이태식 정승희 이두석 윤호동 김풍호 112 본연구에서는양식되고있는잉어와뱀장어에대하여사료에 fluoroquinoloe 계항생제 4 종 (ciprofloxacin, enrofloxacin, norfloxacin, sarafloxacin) 을각각섞어강제경구투여한후체내잔류량을경시적으로파악함으로써항생제의효율적인관리를위한안전성평가의기초자료로제공할목적으로수행하였다. 재료및방법 시약및기기수산용으로사용되는표준품은 ciprofloxacin 은제일제당 ( 주 ) 에서 norfloxacin, enrofloxacin, sarafloxacin 은대성미생물연구소 ( 주 ) 로부터제공받았다. HPLC 용 acetonitrile, methanol 및증류수등용매류는 Merck 사 (Germany) 를사용하였으며, 그외본실험에사용된모든시약은특급혹은분석용이상을사용하였다. Centrifuge (Hanil, Korea), plastic syringe (1 ml, No. 39. Dong-Shin Co., Ltd, Korea) 는시료전처리과정에사용하였고, chromatography system 은 pump (Agilent 1100 series, USA), autosampler (Agilent 1100, USA), DAD (diode array detector, Agilent 1100 series, USA), column (C18, 250 4.6 mm i.d., Shiseido, Japan) 등을사용하였다. 약물투여및시료의채취실험에사용할어류는항균물질투여치료를받은적이없는건강한잉어 (Carp, Cyprinus carpio, 400±50 g) 와뱀장어 (Eel, Anguilla japonica, 250±30 g) 를각각원형수조 ( 지름 150 cm 높이 75 cm) 에넣어서사용하였다. 실험어는 5~7 마리씩을무게를달고, 이를구별하기위하여지느러미를잘라서숫자로표시하고수조에 10 일간순치시켰으며, 실험전날은사료를먹이지않았다. 어류에강제경구투여한항생제혼합사료는일반사료를가루로만들어물과함께반죽한다음어체중당 20 mg/kg b.w. 를계산하여그속에넣었다. 투여용량은제조회사의권고용량 ( 대성미생물연구소 ( 주 ), Korea) 과이미보고되어진용량 (Nouws et al., 1988; Bowser et al., 1992; Park et al., 1996; Ho et al., 1999) 을참고하였는데대개어체중당 5~10 mg/kg b.w. 을투여하였다. 따라서본실험에서는실제양식장에서의투여용량을감안하여앞에서보고한용량보다 2 배정도높은 20 mg/kg b.w. 로정하였고, 만들어진사료는 -20 에서보관하였으며, 일주일이내에사용하였다. 시료의채취방법은원형수조에있는각실험어를작은통에옮겨마취시킨후항생제혼합사료를강제적으로위까지밀어넣은다음다시원형수조로옮겨서토해내는지의여부와마취에서깨어나는지확인하였다. 잉어및뱀장어에 1 회강제경구투여하였으며대조군은일반사료를사용하여위와같은방법으로강제경구투여하였다. 체내의항생제의축적및잔류양상을파악하기위하여잉어및뱀장어에서시간별로 5~7 마리씩혈액 300~500 μl 를채취하여약물의혈중잔류농도변화를 HPLC 로분석하였다. 실험어는경구투여전 (0 시간 ) 과경구투여후 5 시간, 10 시간, 1 일, 2 일, 3 일, 5 일, 7 일, 9 일, 13 일, 20 일, 30 일, 35 일째까지채취하였다. 채취한혈액은 10,000 rpm 에서 5 분간원심분리하고상층을취하여 -80 에보관하였다. 표준용액및이동상조제 Fluoroquinolone 계항균물질표준품 (ciprofloxacin, norfloxacin, enrofloxacin 및 sarafloxacin) 을약 100 mg 를정밀히달아각각 100 ml 용량플라스크에넣고 0.1 N 수산화나트륨소량으로녹인후 methanol 을가하여 1000 μg/ml 농도로만들어표준원액 (stock solution) 으로하였다. 표준원액은밀봉한후냉장보관하였을때약 3 개월간안정하였다. Working solution 은 50 ml 표준원액을시험관에취해 methanol 을가하여 100 ml (500 ppm) 로맞춘다음, 이용액을이동상으로희석하였다. Fluoroquinolone 계항생물질을분리하기위한이동상조성은 Posyniak et al. (1999) 및 Figosos et al. (2000) 의방법을일부변형한 0.1 M phosphoric acid (ph 2.5) 와 acetonitrile 을 85 : 15 의비율로조제하였으며, 측정파장은 278 nm, column 온도는 35 의조건으로실시하였다 (Table 1). Table 1. HPLC conditions for 4 fluoroquinolones determination in carp and eel Item Analysis condition HPLC system Agilent 1100 series Mobile phase 0.1 M phosphoric acid: Acetonitrile= 85:15 (ph 2.5) Detector DAD (Diode array detector, UV 278 nm) Column Shiseido UG 120 type C18, 4.6mm I.D. 250 mm Flow rate 1.0 ml/min Column temperature 35 Injection volume 50 μl 시료전처리및분석혈액에대한시료의전처리과정은 Intorre et al. (2000) 의방법을일부변경하여혈액에대한간편하면서도신속하게추출하였다. 즉, -80 에보관되어있는시료를상온에방치하여녹인후 200 μl 를정확히분취하여동량으로이동상 200 μl 를가한다음균질화 (10,000 rpm, 30 sec) 하였다. 이것을 80 에서 5 분간가열한후냉각시켜 10,000 rpm 에서 10 분간원심분리하여나온상층액을여과 (0.22μm, PTFE) 한후, HPLC 로분석하였다. 표준검량선작성및잔류농도계산 Ciprofloxacin, norfloxacin, enrofloxacin, sarafloxacin 의표준용액의농도를각각단계희석 (0.01 0.05, 0.1, 0.5, 1, 5, 10 μg/ml) 하여 50 μl 를 HPLC 에주입후각농도에대한피크면적으로부터검량선을작성하였다. 시료에서약물잔류농도계산은시료를정제하여칼럼에주입하여표준용액과동일한머무름시간에있는피크의면적값을해당표준물질의회귀방정식에대입하여농도를구한다음아래의식에의해잔류농도를구하였다. 분석한항생제의농도가 10 μg/ml 이상함유된시료는이동상으로희석하여

127 양식잉어및뱀장어에경구투여한 fluroquinolone 계항생제의체내잔류량의변화 625 검량선상의고농도와저농도의사이에놓이도록하였으며 HPLC 의정확도를높이기위하여분석시료간에 1.0 μg/ml 농도의표준용액을주입하여처음주입한표준용액의피크및머무름시간 (retention time) 에대해 10% 이상차이를보이면이동상으로칼럼을세척한뒤분석하였다. 시료에서의측정량 μg 잔류농도 (μg/g) = 시료량 회수율 회수율측정시험방법의회수율을구하기위하여잉어및뱀장어시료에농도를알고있는 ciprofloxacin, norfloxacin, enrofloxacin, sarafloxacin 표준용액 0.1, 0.5, 1.0 μg/ml 을가하여분석하고얻어진크로마토그램의 peak 면적비를이용하여회수율을구하였다 (Causon R, 1997). 결과및고찰 직선성, LOD 및 LOQ Fluoroquinolone 계항생제 4 종을분석시 1/x 에대한가중치로서단순회귀분석하였을때각각 0.01 0.05, 0.1, 0.5, 1, 5, 10 μg/ml 에서직선성을나타내었고, 회귀계수는모두 0.998 이상이었다 (Table 2). Table 2. Linearity and sensitivity data Analyte Intercept Slope r 2 a LOD (μg/ml) b LOQ (μg/g) Ciprofloxacin -0.6907 182.63 0.998 0.04 0.1 Norfloxacin -0.4374 193.87 0.999 0.03 0.05 Enrofloxacin -0.3645 174.82 0.999 0.04 0.1 Sarafloxacin -0.0128 132.23 0.998 0.03 0.05 a LOD, limit of detection; b LOQ, limit of quantitation. Fluoroquinolone 계항생제의검출한계 (LOD, Limit of Detection) 및정량한계 (LOQ, Limit of Quantitation) 를살펴보면 ciprofloxacin 과 enrofloxacin 은 0.04, 0.1 μg/g 이었으며, norfloxacin 과 sarafloxacin 은 0.03, 0.05 μg/g 으로나타나이들두항생제는 ciproflxoacin 과 enrofloxacin 보다검출율이약간낮았으나, 잔류량변화를관찰하는데문제는없었다. Fig. 1 과 Fig. 2 는잉어및뱀장어에 fluoruqinolone 계항생제 4 종을첨가하여전처리한후 HPLC 로측정한것으로항생제 peak 주위에방해 peak 가없이아주양호한 chromatogram 을나타내었다. Fig. 1. Chromatograms of fluoroquinolones obtained with (a) blank carp muscle tissue, (b) extract from carp muscle tissue fortified with norfloxacin, ciprofloxacin, enrofloxacin and sarafloxacin at 0.5 μg/g, (c) standard solution containing norfloxacin, ciprofloxacin, enrofloxacin and sarafloxacin at 0.5 μg/g. Fig. 2. Chromatograms of fluoroquinolones obtained with (a) blank eel muscle tissue, (b) extract from eel muscle tissue fortified with norfloxacin, ciprofloxacin, enrofloxacin and sarafloxacin at 0.5 μg/g, (c) standard solution containing norfloxacin, ciprofloxacin, enrofloxacin and sarafloxacin at 0.5 μg/g.

626 조미라 박큰바위 이희정 김지회 이태식 정승희 이두석 윤호동 김풍호 112 Table 3. Average recovery (%) of fluoroquinolones from tissue of carp and eel Fluoroquinolones Tissue Fortification lever (μg/g) ±S.D. 0.1 0.5 1.0 Ciprofloxacin Blood 92.6±2.2 96.5±1.9 95.5±1.0 Muscle 94.0±5.4 91.2±3.6 93.0±3.0 Carp Norfloxacin Blood 96.6±2.7 96.1±2.1 96.9±1.1 Muscle 96.2±1.1 96.2±0.7 97.7±0.5 Enrofloxacin Blood 96.3±1.6 95.4±0.6 98.6±2.4 Muscle 93.7±0.8 94.2±0.8 92.6±1.2 Sarafloxacin Blood Muscle 96.0±1.0 93.8±0.9 92.8±0.3 92.1±1.7 93.5±0.8 93.7±1.9 Ciprofloxacin Blood 96.5±1.6 96.0±2.0 96.4±1.9 Muscle 91.4±0.8 94.3±2.4 94.1±1.0 Eel Norfloxacin Blood 93.2±0.9 93.0±1.1 96.5±0.9 Muscle 94.0±0.6 93.0±1.1 94.1±0.4 Enrofloxacin Blood 96.5±0.8 96.0±0.3 93.9±0.6 Muscle 92.4±1.3 91.2±0.4 92.7±1.1 Sarafloxacin Blood 93.7±1.0 95.9±3.9 93.6±0.7 Muscle 92.4±0.5 92.9±0.5 90.4±0.7 * Average recovery was obtained from 5 replications. 회수율잉어및뱀장어에각각 5 마리씩항생제최종농도가 0.1 μ g/g, 0.5 μg/g, 1.0 μg/g 이되게첨가하여추출, 정제하여분석하였을때회수율은 Table 3 과같다. 잉어에대한회수율은 ciprofloxacin 의경우 91.2~96.5%, norfloxacin 은 96.1~97.7% 이고, enrofloxacin 은 92.6~98.6% 이었으며, sarafloxacin 은각각 92.1~96.0% 를나타내었다. 뱀장어에대한회수율은 ciprofloxacin 의경우 91.4~96.5% 이며, norfloxacin 은 93.0~96.5% 이고, enrofloxacin 은 91.2~96.5% 이었으며, sarafloxacin 은각각 90.4~95.9% 를나타내었다. 따라서잉어와뱀장어의회수율은평균 90% 이상의양호한값을나타내었으며, 각각의항생제들과비교해볼때 ciprofloxacin, norfloxacin, enrofloxacin 이 sarafloxacin 보다약간높았으며, 근육시료보다혈액시료에서추출하였을때회수율이대체로높게나타났다. 경구투여된 fluoroquinolone 계항생제의체내잔류량변화잉어와뱀장어에체중 1 kg 당 20 mg 이되도록 ciprofloxacin, enrofloxacin, norfloxacin 및 sarafloxacin 을각각경구투여하였을때시간의경과에따른잔류량변화를 Table 4 및 Table 5 에각각나타내었다. 잉어에대한 ciprofloxacin, norfloxacin, enrofloxacin 및 sarafloxacin 약물의잔류형태를살펴보면 cirprofloxacin, norfloxacin 및 sarafloxacin 은 10 시간째높은잔류분포를나타내었고, enrofloxacin 은 1 일째되어서높은잔류농도를보여서항생제마다차이를보였으며개체간차이도큰것으로나타났다 (Table 4). 그후 2 일째까지급격히감소하는양상을보이다가 3 일째 ciprofloxacin 는 2.23±0.89 μg/ml, norfloxacin 은 1.85±0.32 μg/ml, enrofloxacin 은 2.06±0.53 μ g/ml 과 sarafloxacin 은 2.00±0.33 μg/ml 로 1.0 μg/ml 의농도로잔류하였다. 5 일째부터완만하게감소하기시작하여 ciprofloxacin, norfloxacin 및 sarafloxacin 은 20 일째각각정량한계 (LOQ) 이하의농도로나타났으며, enrofloxacin 는 20 일째까지 0.04±0.01 μg/ml 농도로나타나다가 30 일째정량한계이하로낮아졌다. 뱀장어에대한 ciprofloxacin, norfloxacin, enrofloxacin 및 sarafloxacin 약물의잔류형태를살펴보면네가지약제모두 10 시간째에서공통적으로높은잔류농도를나타내었으며그후 5 일째까지급격히감소하는양상을보이다가 7 일째에는완만하게감소하기시작하여 ciprofloxacin 및 sarafloxacin 은 13 일째각각 0.14±0.02 μg/ml 과 0.09±0.02 μg/ml 농도로나타난다음 20 일째정량한계이하로낮아졌다 (Table 4). Norfloxacin 의경우는 20 일까지 0.07±0.01 μg/ml 의농도로잔류하다가 30 일째는정량한계이하로낮아졌으며, enrofloxacin 은 30 일까지 0.05±0.007 μg/ml 의농도로검출되었다가 35 일째정량한계이하로낮아져뱀장어에서도잉어와마찬가지로 enrofloxacin 이가장길게잔류하는것으로나타났다. Table 4. Concentration of fluoruquinolones in plasma of carp after oral administration of a single dose of 20 ml/kg b.w. (μg/g) Time Concentration (μg/ml) ± S.D. Ciprofloxacin Enrofloxacin Norfloxacin Sarafloxacin 0 hr - - - - 5 hr 5.73±1.24 5.13±0.44 4.61±0.20 4.98±0.21 10 hr 11.03±2.86 9.02±0.49 9.10±1.60 9.81±1.72 1 day 10.16±1.77 9.37±1.10 8.49±0.68 8.50±0.75 2 day 4.47±1.18 3.83±0.57 3.57±0.25 3.85±0.27 3 day 2.23±0.89 2.06±0.53 1.85±0.32 2.00±0.33 5 day 0.99±0.49 0.96±0.42 0.74±0.04 0.81±0.07 7 day 0.35±0.07 0.32±0.08 0.28±0.07 0.33±0.06 9 day 0.25±0.04 0.20±0.05 0.19±0.03 0.21±0.04 13 day 0.12±0.03 0.09±0.01 0.09±0.01 0.10±0.02 20 day - 0.04±0.01 - - 30 day - - - - 35 day - - - - * ; -, not detected. Table 5. Concentration of fluoruquinolones in plasma of eel after oral administration of a single dose of 20 ml/kg b.w. (μg/g) Time Concentration (μg/ml) ± S.D. Ciprofloxacin Enrofloxacin Norfloxacin Sarafloxacin 0 hr - - - - 5 hr 6.42±0.27 6.36±0.54 6.04±0.26 4.39±0.19 10 hr 12.65±2.23 11.18±0.61 11.91±2.10 8.74±1.53 1 day 10.97±0.97 9.96±0.83 10.33±0.92 7.66±0.62 2 day 4.97±0.35 4.35±0.48 4.68±0.33 3.39±0.26 3 day 2.57±0.44 2.17±0.15 2.42±0.42 1.77±0.31 5 day 1.03±0.06 1.01±0.11 0.97±0.05 0.72±0.16 7 day 0.41±0.08 0.37±0.03 0.38±0.08 0.28±0.06 9 day 0.30±0.05 0.19±0.05 0.27±0.03 0.20±0.03 13 day 0.14±0.02 0.11±0.03 0.14±0.04 0.09±0.02 20 day - 0.09±0.015 0.07±0.01-30 day - 0.05±0.007 - - 35 day - - - - * ; -, not detected.

127 양식잉어및뱀장어에경구투여한 fluroquinolone 계항생제의체내잔류량의변화 627 Nouws et al. (1988) 은본연구와약간투여방법이다르지만, 잉어, 메기및무지개송어에 ciprofloxacin을 15 mg/kg의정맥및근육주사를한후잔류량을본결과최고농도도달시간이투여후 1 시간이었지만, 본연구는사료에섞어먹인항생제인관계로최고도달농도는조금긴 10시간이었다. 이는어류에직접투여하여잔류되는시간과사료에혼합된항생제가위로들어가서조직으로흡수될때까지잔류되는시간의차이가나는것으로사료되었다. Xu et al. (2006) 의경우틸라피아에 ciprofloxacin와 enrofloxacin를각각 7일간 50 mg/kg b.w. 로경구투여하고시간별로시료를채취하여분석한결과축적량은항생제마다다소차이가있었으나투약후모두 16일에는정량한계인 0.1 mg/kg이하로잔류하여본연구도이와비슷한경향을나타내었다. Martinsen and Horsberg (1995) 의보고는 10 mg/kg b.w. 를경구투여한연어 (Atlantic Salmon) 에서 sarafloxacin과 enrofloxacin을시간에따라축적되는농도를비교한결과 5일째 sarafloxacin은 0.01 μg/ml 이하이었고 enrofloxacin은 0.05 μg/ml로나타나본연구결과와는다른농도차이를보였는데이는수온및개체차에따른차이에의한것으로사료되었다. 또한 enrofloxacin의경우 Treves-Brown (2000) 은해수어류에서의 enrofloxacin 잔류기간이담수어류보다더길게한다고하여앞전에보고했던 Kim et al. (2009) 의넙치와조피볼락의 fluoroquinolone 잔류량을본연구결과와비교한다면거의유사한양상을보인것으로추측되었다. 이와같이 fluoroquinolone계항생제의축적과잔류농도의차이는시험시어종, 개체차, 수온, 환경등에영향을많이받는것으로나타났으며, 활동성이큰잉어가뱀장어보다조금더잔류시간이긴것으로나타났다. 따라서본연구를통하여현재는판매금지되었지만과거에양식어류에광범위하게사용되었던 fluoroquinolone계항생제를경구투여하여잔류량변화를조사함으로서향후양식어류에사용되는다른항생제들의잔류량분포연구를촉진시키고, 항생제의효율적인사용을위하여잔류및내성균의출현을사전방지하고안정성및유효성검증에필요한기초자료로활용될것으로기대한다. 사 본연구는국립수산과학원수출패류생산해역및수산물위생조사연구의연구비지원에의해수행되었습니다 ( 관리번호 : RP-2009-FS-003). 사 참고문헌 Bowser PR, Wooster GA, Stleger J and Babish JG. 1992. Pharmacokinetics of enrofloxacin in fingerling rainbow trout (Oncorgynchus mykiss). J Vet Pharmaco Therap 15, 62-71. Causon R. 1997. Validation of chromatographic methods in biomedical analysis viewpoint and discussion. J Chromatogr B 689, 175-180. Chevalier R, Gerald JP and Michel C. 1981. Distribution et cinetique tissulaire de la flumequine chez truite arc-en-ciel (salmo gairdneri, Richardson). Recherche de residus. Rev Med Vet 132, 831. Figosos PG., Revesado PR, Cadahia O, Fente CA, Vazquez BI, Franco CM, Cepeda A. 2000. Determination of quinolones in animal tissues and eggs by high-performance liquid chromatography with photodiode-array detection. J Chromatog A 871, 31-36. Herikstad H, Hayers P, Mokhtar M, Fracaro ML, Threlfall EJ and Angulo FJ. 1997. Emerging quinoloneresistant Salmonella in the USA. Emerg Infect Dis 3, 371-372. Heo GJ, Shin KS and Lee MH. 1992. Diseases of aquaculture animals and prevention of drug residues. Kor J Food Hyg 7, S7-S19. Ho SP, Cheng CF and Wang WS. 1999. Pharmacokinetic and depletion studies of sarafloxacin after oral administration to eel (Anguilla anguilla). J Vet Med Sci 61, 459-463. Kasuga Y, Sugitani A, Yamada F, Arai M and Morikawa S. 1984. Oxolinic acid residues in tissues of cultured rainbow trout and ayu fish. J Food Hyg Soc Jpn 25, 512-615. Kim PH, Lee DS, Kim JW, Park MS, Kim DS and Jo MR. 2009. Residues of fluoroquinolones in Olive flounder (Paralichthys olivaceus) and Black Rockfish (Sebastes schlegeli) following oral administration. Kor J Fish Aquat Sci 42, 329-334. Nouws JF, Grondel JL, Schutte AR and Laurensen J. 1998. Pharmacokinetics of ciprofloxacin in carp, African catfish and rainbow trout. Vet Qrart 10, 211-216. Park SC, Yun HI and Oh TK. 1996. Comparative pharmacokinetics and tissue distribution of norfloxacin-glycine acetate in flounder, (Paralichthys olivaceus) at two different temperatures. J Vet Med Sci 58, 1039-1040. Intorre L, Cecchini S, Bertini S, Cognetti Varriale AM, Soldani G and Mengozzi G. 2000. Pharmacokinetics of enrofloxacin in the seabass (Dicentrarchus labrax). Aquaculture 182, 49-59. Martinsen B. and Horsberg E. 1995. Comparative singledose pharmacokinetics of four quinolones, oxolinic acid, flumequine, sarafloxacin and enrofloxacin, in Atlantic Salmon (Salmo salar) held in seawater at 10. Antimicrob Agents Chemother 39, 1059-1064. Markwardt MN and Klontz GW. 1998. A method to eliminate the symptomatic carrier state of Aeromonas salmonicida in salmonids. J Fish Dis 12, 317.

628 조미라 박큰바위 이희정 김지회 이태식 정승희 이두석 윤호동 김풍호 112 Nouws JP, Grondel JL, Schutte AR and Laurensen J. 1988. Pharmacokinetics of ciprofloxacin in carp, African catfish and rainbow trout. Vet Q 10, 211-216. Posyniak A, Zumdzki J, Semeniuk S, Niedzielska J and Eillis R. 1999. Determination of fluoroquinolone residues in animal tissues by liquid chromatography. Biomed Chromatogr 13, 279-285. Smith KE, Besser JM, Hedberg CW, Leano FT, Bender JB, Wicklund JH, Johnson BP, Moore KA and Osterholm MT. 2003. Quinolone-resistant Campylobacter jejumi infections in Minnesota. New Engl J Med 340, 1525-1532. Treves-Brown KM. 2000. Appiled fish pharmacology. Charpter 10. Quinolones and Fluoroquinolones. Kluwer Academic publishers, London, U.K., 117-142. Xu W, Zhu X, Wang X, Deng L and Zhang G. 2006. Residues of enrofloxacin, furazolidone and their metabolites in Nile tilapia (Oreochromis niloticus). Aquaculture 254, 1-8. 2010 년 9 월 6 일접수 2010 년 10 월 4 일수정 2010 년 12 월 3 일수리