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Plasma and muscle tissue disposition of enrofloxacin in Nile tilapia ( Oreochromis niloticus ) after intravascular, intraperitoneal, and oral administrations
Abstract
The aim of the study was to investigate the plasma and muscle pharmacokinetic of enrofloxacin (ENR) and its active metabolite ciprofloxacin (CIP) in Nile tilapia (Oreochromis niloticus) following single intravascular (IV), intraperitoneal (IP), or oral (PO) administration at 30 ± 1 °C. In this study, 234 healthy Nile tilapia (120-150 g) were used. The fish received a single IV, IP, or PO treatment of ENR at a dose of 10 mg/kg. The plasma and muscle tissue concentrations of ENR and CIP were measured using high-performance liquid chromatography with fluorescence detection and were evaluated using non-compartmental analysis. The elimination half-life, volume of distribution at steady state, and total body clearance of ENR were 21.7 h, 2.69 L/kg, and 0.09 L/h/kg, respectively. The peak plasma concentrations of ENR after IP or PO administration were 6.11 and 4.21 µg/mL at 0.25 and 2 h, respectively. The bioavailability of ENR for IP or PO routes was 78% and 86%, respectively. AUC(0-120)muscle/AUC(0-120)plasma ratios following the IV, IP, or PO administrations were 1.43, 1.49, and 1.07, respectively. CIP was detected after all routes, but the AUC0-last ratios of CIP to ENR were <1.0% for plasma and muscle. ENR was detected up to 120 h following the IV, IP, or PO administrations. The long residence time of ENR after single IV, IP, or PO administration ensured the plasma concentration was ≥1 × MIC for bacteria with threshold MIC values of 0.92, 0.72, and 0.80 μg/mL over the whole 120 h observed. However, further studies are necessary to determine the optimum pharmacokinetic/pharmacodynamics data of ENR for the treatment of infections caused by susceptible bacteria in tilapia.
... The pharmacokinetics of enrofloxacin have been studied in fish species such as yellow cat fish (Jia et al., 2924), northern snake head fish (Zhang et al., 2023), Nile tilapia (Corum et al., 2022), crucian carp (Shan et al., 2018), snakehead fish (Fang et al., 2016), rainbow trout (Urzua et al., 2020;Lucchetti et al.,2004), large yellow croaker , red pacu (Lewbart et al., 1997), and largemouth bass (Shan et al., 2020). However, there were no reports on the pharmacokinetics of enrofloxacin in rohu. ...
... Several reports showed a wide range of Tmax in various fish species. Following a single oral dose of 10 mg/kg body weight, the values recorded in different fish species were 2 h in Nile tilapia (Corum et al, 2022), 3.31 hours in snakehead fish (Fang et al., 2016), 0.68 hours in Crucian carp (Shan et al., 2018), and 0.25 hours in Koi carp (Udomkusonsri et al., 2007). The Tmax observed in the present study was higher than the reported values, indicating a slower rate of absorption of enrofloxacin in rohu. ...
The pharmacokinetics of enrofloxacin was studied in rohu (Labeo rohita) after single intramuscular or oral administration at 10 mg/kg body weight and following bath exposure at the concentration of 5 mg/L for 5 h. Blood samples were collected at predetermined time intervals. The plasma concentrations of enrofloxacin were determined by high performance liquid chromatography. The pharmacokinetic parameters were analyzed using a non-compartmental method. After intramuscular administration, a Cmax of 5.602 μg/ml was observed at 4 h (Tmax). After oral administration and bath exposure, a Cmax of 3.380 μg/ml at 8 h (Tmax) and 4.785 μg/ ml at 4 h (Tmax), respectively, were observed. AUC0-∞ following intramuscular, oral, and bath exposure were determined to be 166.51, 76.69, and 75.45 μg.h.ml-1, respectively. Elimination half-life (t1/2) was found to be 43.31, 34.65, and 21.66 h following intramuscular, oral, and bath exposure, respectively. The volume of distribution (Vd/F) was found to be maximum after oral administration (6.52 L/kg) as compared to the intramuscular route (3.75 L/kg) and bath exposure (2.07 L/kg). The results of our study indicate that enrofloxacin was well absorbed, widely distributed, and slowly eliminated in rohu following all three routes of administration and a dosage of 10 mg/kg for intramuscular or oral route and 5 mg/L for 5 h for bath immersion would be sufficient to produce plasma concentrations for successful treatment of fish pathogenic strains with MIC ≤ 0.3μg/ ml.
... Danofloxacin is found in higher concentrations in the liver and kidney of fish, possibly due to the role of these organs in excretion. This ratio > 1 indicates that the drug has good tissue affinity in fish [39]. The AUC tissue /AUC plasma ratios of danofloxacin in liver, kidney, and muscle of rainbow trout were greater than 1. ...
Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t1/2ʎz), volume of distribution (Vdarea/F), total clearance (CL/F), peak concentration (Cmax), and area under the plasma concentration–time curve (AUC0–last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t1/2ʎz, AUC0–last and Cmax increased concomitantly with trout growth, whereas CL/F and Vdarea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. Cmax and AUC0–last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue.
... Since aquatic animals live in aquatic environments, the selection of a suitable drug administration method can enhance the efficiency of drug utilization. To date, routes of drug administration have included oral gavage, injection, medicated feed, and medicated bath (Corum et al. 2022;Gore et al. 2005;Xu et al. 2022). Oral gavage has generally been used in lab experiments, but not in real aquaculture scenarios because of the large number of fish being treated. ...
Enrofloxacin (EF) is a broad-spectrum and highly efficient antibiotic commonly used for treating diseases in aquatic animals. However, its abuse in aquaculture applications often leads to excess residue in tissues of grass carp (Ctenopharyngodon idella). Hence, this study aimed to estimate the withdrawal time (WT) of EF and its metabolite of ciprofloxacin (CF) administered medicated feed in natural culture environments and conduct a risk assessment. Plasma and tissue samples were gathered at appropriate time points and detected by high-performance liquid chromatography. The data homogeneity was evaluated by Bartlett’s test and Cochran’s test. The linearity of the regressed line was evaluated by visual inspection and F test. Outliers were estimated on a normal probability scale by plotting the standardized residual versus their cumulative frequency distribution. Finally, the WT was calculated to be 51 days in muscle + skin based on the maximum residue limit of 100 µg/kg. After 51 days, the concentration of EF and CF fell below 10 µg/kg. The estimated daily intake was calculated to be 0.009 µg/kg/d. Hazard quotient was computed to be 0.002, which was far below one. These results suggested that calculated WT of EF could ensure the safety of products from grass carp for humans.
... Pharsight Corporation, Scientific Consulting Inc., North Carolina, USA). Because different animals were used at each sampling time, the pharmacokinetic calculation was determined by non-compartmental analysis of the mean concentration values at the sampling times for each sex in the group [27,28]. For both groups, the terminal elimination half-life (t1/2ʎz), area under the curve (AUC), mean residence time (MRT), total body clearance (CL/F) and volume of distribution (Vdarea/F) were calculated. ...
Abstract: Background: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial dis�eases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simul�taneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects
the pharmacokinetics of MFX in rats.
Objectives: The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics
of MFX in male and female rats.
Methods: A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and
MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were
administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the high�performance liquid chromatography-UV and pharmacokinetic parameters were evaluated by non�compartmental analysis.
Results: Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to
8 h (AUC0-8) and peak concentration (Cmax) of MFX in rats, while it significantly decreased the total body
clearance (CL/F). When female and male rats were compared, significant differences were detected in
AUC0-8, Cmax, CL/F and volume of distribution. The AUC0-8lung/AUC0-8plasma ratios of MFX were calculated as
1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively.
Conclusion: MFX was highly transferred to the lung tissue and this passage was remarkably higher in male
rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats
but did not change its passage to the lung. However, there is a need for a more detailed investigation of the
difference in the pharmacokinetics of MFX in male and female rats.
... Pharmacokinetic non-compartmental analysis of OTC concentration-time data was analyzed using the WinNonlin 6.1.0.173 software (Pharsight Corporation, Scientific Consulting Inc., Raleigh, NC, USA). Pharmacokinetic parameters of OTC were calculated from the mean plasma concentration values collected at each sampling time, as reported in previous studies [20,21]. The pharmacokinetic parameters calculated included the area under the plasma concentration-time curve (AUC), AUC extrapolated from tlast to ∞ in % of the total AUC (AUC extrap %), volume of distribution at steady state (V dss = Cl T × MRT), apparent volume of distribution (V darea ), total body clearance (Cl T = Dose/AUC), terminal elimination half-life (t 1/2 ...
Simple Summary
Determination of the pharmacokinetics of oxytetracycline (OTC) at single and multiple oral doses revealed its long half-life, very low bioavailability, and strong accumulation in rainbow trout. The withdrawal time (WT) for the safe consumption of rainbow trout muscle+skin varied according to the guidelines set by regulatory authorities in different countries. This study improves the establishment of the optimal dosing regimen following OTC multiple administration and the determination of the appropriate WT for the safety of rainbow trout consumption.
Abstract
The aim of this study was to compare the pharmacokinetics of oxytetracycline (OTC) following single- (60 mg/kg) and multiple-dose oral administrations (60 mg/kg, every 24 h for 7 days) in rainbow trout. It also aimed to determine bioavailability after a single dose and tissue residues and withdrawal times after multiple doses. This study was carried out on 420 rainbow trout at 9 ± 0.8 °C. This study was carried out in two stages: single-dose (intravascular and oral) and multiple-dose treatment. The OTC concentrations in plasma and tissues were measured by high-performance liquid chromatography and analyzed by a non-compartmental method. The withdrawal time (WT) was estimated using the WT 1.4 software. OTC exhibited a long terminal elimination half-life (t1/2ʎz) after IV and oral administration. The oral bioavailability of OTC was very low (2.80%). In multiple-dose treatment, t1/2ʎz, the area under the plasma concentration–time curve and peak plasma concentration increased significantly after the last day compared to the first day. OTC showed strong accumulation after multiple doses with a value of 5.33. OTC concentrations were obtained in the order liver > kidney > muscle+skin > plasma. At 9 ± 0.8 °C, the WT calculated for muscle+skin was 56 days for Europe and 50 days for China, respectively. The t1/2ʎz (68.94 h) and time (68 h) above the 1 µg/mL MIC following a single OTC dose may support the extension of the 24 h dosing interval following multiple dosing. However, further studies are required to determine the optimal dosage regimen in multiple-dose OTC treatment in the treatment of infections caused by susceptible pathogens.
... Prior studies identified a high oral bioavailability (86%) of enrofloxacin with extensive penetration into muscle of Nile tilapia (Corum et al., 2022); oral bioavailability was 55.5% in Atlantic salmon (Martinsen and Horsberg, 1995) and 64.5% in Korean catfish . Extensive muscle penetration was further reported in rainbow trout, as well as common and crucian carp (Kyuchukova et al., 2015;Fan et al., 2017;Shan et al., 2018;Urzúa et al., 2020). ...
... Using the WinNonlin 6.1.0.173 software program (Pharsight Corporation, Scientific Consulting Inc., Sunnyvale, NC, USA), the plasma concentration-time curves of doxycycline were plotted. After oral administration, pharmacokinetic parameters were determined via non-compartmental analysis using mean plasma concentrations of doxycycline collected at each sampling time [25][26][27]. After the doxycycline administration, apparent volume of distribution (V darea /F), total body clearance (CL/F, area under the concentration-time curve (AUC), terminal elimination half-life (t 1/2Lz ), AUC extrapolated from t last to ∞ in % of the total AUC (AUC extrap %), and mean residence time (MRT) were determined. ...
The purpose of this study was to compare the pharmacokinetics, tissue residues, and withdrawal times of doxycycline after oral administration in rainbow trout reared at 10 and 17 °C. Fish received a 20 mg/kg oral dose of doxycycline after a single or 5-day administration. Six rainbow trout were used at each sampling time point for plasma and tissue samples, including liver, kidney, and muscle and skin. The doxycycline concentration in the samples was determined using high-performance liquid chromatography with ultraviolet detector. The pharmacokinetic data were evaluated by non-compartmental kinetic analysis. The WT 1.4 software program was used to estimate the withdrawal times. The increase of temperature from 10 to 17 °C shortened the elimination half-life from 41.72 to 28.87 h, increased the area under the concentration–time curve from 173.23 to 240.96 h * μg/mL, and increased the peak plasma concentration from 3.48 to 5.50 μg/mL. At 10 and 17 °C, the doxycycline concentration was obtained in liver > kidney > plasma > muscle and skin. According to the MRL values stated for muscle and skin in Europe and China (100 μg/kg) and in Japan (50 μg/kg), the withdrawal times of doxycycline at 10 and 17 °C were 35 and 31 days, respectively, for Europe and China and 43 and 35 days, respectively, for Japan. Since temperature significantly affected pharmacokinetic behavior and withdrawal times of doxycycline in rainbow trout, temperature-dependent dosing regimens and withdrawal times of doxycycline might be necessary.
Deniz ürünleri üretimi, milyonlarca insana istihdam ve geçim sağlayan kritik bir küresel endüstridir. Sektördeki üretim teknolojilerinin yoğunlaşması, deniz ürünleri üretimindeki arz-talep açığını kapatmak için ortaya çıkmıştır, ancak potansiyel halk sağlığı tehditlerine ilişkin endişeler gündeme gelmiştir. Örneğin, su ürünleri yetiştiriciliği ortamlarında artan stok yoğunlukları balıklarda stresin artmasına yol açarak patojen çoğalmasına elverişli bir ortam yaratmıştır. Antibiyotikler balıklarda ve diğer hayvanlarda bakteriyel enfeksiyonların tedavisinde ve önlenmesinde yaygın olarak kullanılmaktadır. Ancak antibiyotiklerin insan ve hayvan sağlığına zararlı etki yapma riski bulunmaktadır. Balıklarda ve diğer su hayvanlarında, ayrıca su ortamında ve diğer ekolojik nişlerde antibiyotiklere dirençli bakterilerin ortaya çıkması, ilaca dirençli bakterilerin ve aktarılabilir direnç genlerinin rezervuarlarını oluşturmuştur. İnsan patojenlerindeki antimikrobiyal ajanlara karşı direnç, insan enfeksiyonları sırasında tedavi seçeneklerini ciddi şekilde sınırlandırmaktadır. Bu derleme, su ürünleri yetiştiriciliğinde yaygın olarak kullanılan antibiyotik türleri, antibiyotik uygulaması, antibiyotik test teknikleri ve su, balık ve sedimentteki antibiyotik direnci hakkındaki bilgileri bir araya getirmektedir. Antibiyotik direnciyle mücadelede karşılaşılan zorluklar, stratejiler ve kısıtlamaların yanı sıra su ürünleri yetiştiriciliğinde antibiyotik kullanımına yönelik beklentiler de tartışılmaktadır.
The aim of this study was to determine pharmacokinetics of florfenicol and its metabolite florfenicol amine after a single (30 mg/kg) intravenous (IV) and oral administration of florfenicol in chukar partridges. It also aimed to investigate tissue residue and withdrawal time of florfenicol after multiple‐dose (30 mg/kg, every 24 h for 5 days) oral administration. The research was carried out in two stages: pharmacokinetics and residue. Plasma and tissue concentrations of florfenicol and florfenicol amine were determined by HPLC. The elimination half‐life of florfenicol was 5.25 h for IV and 5.44 h for oral. The volume of distribution at a steady state and total body clearance of florfenicol were 0.38 L/kg and 0.07 L/h/kg, respectively, after IV administration. The peak plasma concentration and bioavailability for oral administration were 45.26 ± 4.06 and 51.55%, respectively. After multiple‐dose oral administration, the highest concentration was detected in the liver (9.21 μg/g) for florfenicol and in the kidney (0.67 μg/g) for florfeniol amine. The calculated withdrawal period of florfenicol was determined as 6, 3, 4, and 5 days for muscle, liver, kidney, and skin + fat, respectively. These data indicate that a 6‐day WT after multiple‐dose administration of florfenicol in chukar partridges can be considered safe for human consumption.
Flunixin's pharmacokinetics, bioavailability, and plasma protein binding were examined in rainbow trout. The experiment involved 252 rainbow trout ( Oncorhynchus mykiss ) maintained at 12 ± 0.6°C. Flunixin was administered to rainbow trout via intravascular (IV), intramuscular (IM), and oral routes at a dosage of 2.2 mg/kg. Plasma samples were collected at times 0 (control), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h. High‐pressure liquid chromatography‐ultraviolet was employed to quantify flunixin concentrations. The elimination half‐life ( t 1/2ʎz ) for flunixin was 8.37 h for IV, 8.68 h for IM, and 8.76 h for oral. The t 1/2ʎz was similar between administration groups. The volume of distribution at a steady state and total body clearance were 55.81 mL/kg and 6.83 mL/h/kg, respectively, after IV administration. The mean peak plasma concentration was 6.24 ± 0.41 μg/mL at 4 h for oral administration and 13.98 ± 0.86 μg/mL at 2 h for IM administration. The in vitro protein binding ratio of flunixin in rainbow trout plasma was 96.34 ± 2.29%. The bioavailability of flunixin after oral (25.74%) administration was lower than that after IM (66.70%) administration. Thus, developing an oral pharmaceutical formulation that can be administered with feed and has high bioavailability could enhance the therapeutic effect.
Objective
The aim of this study was to determine the plasma pharmacokinetics of oxytetracycline (OTC) in rainbow trout ( Oncorhynchus mykiss ) of different body sizes.
Methods
The research was carried out on three groups as small (30–50 g), medium (90–110 g) and large (185–215 g) body sizes at 8 ± 0.5 °C. OTC was administered orally at a dose of 60 mg/kg to all groups. Blood samples were taken at 19 different sampling times until the 384 h after oxytetracycline administration. The plasma concentrations of OTC were measured using high pressure liquid chromatography-ultraviolet and pharmacokinetic parameters were evaluated using non-compartmental analysis.
Results
OTC was detected in small-body sized fish until the 336 h and in medium and large-body sized fish until the 384 h. The elimination half-life of OTC was 85.46, 87.24 and 86.98 h in the small, medium and large body size groups, respectively. The peak plasma concentration increased from 0.66 to 1.11 µg/mL, and the area under the plasma concentration-versus time curve from zero (0) h to infinity (∞) increased from 87.86 to 151.52 h*µg/mL, in tandem with the increase in fish body size. As fish body size increased, volume of distribution and total body clearance decreased.
Conclusion
These results show that the pharmacokinetics of OTC vary depending on fish size. Therefore, there is a need to reveal the pharmacodynamic activity of OTC in rainbow trout of different body sizes.
Background
Antibiotics and bronchodilator drugs can be used together in respiratory distress caused by bacterial infections. Levofloxacin (LVX) and Salbutamol (SLB) can be used simultaneously in respiratory distress. However, there have been no investigations on how the concurrent use of SLB can affect the pharmacokinetics of LVX in rats.
Objective
The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats.
Methods
A total of 132 rats were randomly assigned to two groups: LVX (n=66) and LVX+SLB (n=66). LVX (intraperitoneal) and SLB (oral) were administered to rats at doses of 50 and 3 mg/kg, respectively. The concentrations of LVX in the plasma and lungs were determined through the utilization of high-performance liquid chromatography along with UV. Pharmacokinetic parameters were assessed by non-compartmental analysis.
Results
The area under the curve from 0 to 16 h (AUC0−16), terminal elimination half-life, volume of distribution, total body clearance, and peak concentration of LVX in the plasma were 42.57 h*μg/mL, 2.32 h, 3.91 L/kg, 1.17 L/h/kg, and 23.96 μg/mL, respectively. There were no alterations observed in the plasma and lung pharmacokinetic parameters of LVX when co-administered with SLB. The AUC0−16 lung/AUC0−16 plasma ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively.
Conclusion
The concentration of LVX in lung tissue was higher than that in plasma. SLB administration to rats did not affect the plasma and lung pharmacokinetics and lung penetration ratio of LVX. There is a need to reveal the change in the pharmacokinetics of LVX after multiple administration of both drugs and after administration of SLB by different routes.
Background
Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target-age animals
Objective
To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep.
Methods
The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC–UV and analyzed using a non-compartmental method.
Results
ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep.
Conclusion
The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0–24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.
The pharmacokinetic of enrofloxacin was investigated in brown trout (Salmo trutta) following oral administration of 10, 20, and 40 mg/kg doses at 11 ± 1.5 °C. Furthermore, MICs of enrofloxacin against Aeromonas hydrophila and A. sobria were determined. The plasma concentrations of enrofloxacin and ciprofloxacin were determined using HPLC–UV and analyzed by non-compartmental method. Following oral administration at dose of 10 mg/kg, total clearance (CL/F), area under the concentration–time curve (AUC0−∞) and peak plasma concentrations (Cmax) were 41.32 mL/h/kg, 242.02 h*μg/mL and 4.63 μg/mL, respectively. When compared to 10 mg/kg dose, the dose-normalized AUC0–∞ and Cmax were increased by 56.30% and 30.08%, respectively, while CL/F decreased by 38.4% at 40 mg/kg dose, suggesting the non-linearity. Ciprofloxacin was not detected in the all of plasma samples. The MIC values of enrofloxacin were ranged 0.0625–4 μg/mL for A. hydrophila and 0.0625–2 μg/mL for A. sobria. The oral administration of enrofloxacin at 10 (for 192 h) and 20 (for 240 h) mg/kg doses provided the AUC of enrofloxacin equal to 1.23 and 1.96-fold MICs, respectively, for A. hydrophila and A. sobria with the MIC90 values of 1 µg/mL. However, further researches are needed on the PK/PD study of enrofloxacin for the successful treatment of infections caused by A. hydrophila and A. sobria in brown trout.
The Philippines is one of the significant contributors to world fisheries. In 2018, the total production from three sectors, e.g., aquaculture, municipal, and commercial fisheries, was about 4.36 million MT. With this, the Philippines ranked 13th as the top fish-producing country and placed 4th as the major seaweed producer worldwide. The total export earnings of the country from the fisheries sector was US$1.6 billion. The Philippine fisheries sector is an essential contributor to the national economy, providing income from foreign exchange and livelihood sources to almost 2 million Filipino fisherfolks. This review aimed to provide an overview of fisheries and aquaculture in the Philippines.
Pharmacokinetic/pharmacodynamic (PK/PD) modelling is the initial step in the semi-mechanistic approach for optimizing dosage regimens for systemically acting antimi-crobial drugs (AMDs). Numerical values of PK/PD indices are used to predict dose and dosing interval on a rational basis followed by confirmation in clinical trials. The value of PK/PD indices lies in their universal applicability amongst animal species. Two PK/PD indices are routinely used in veterinary medicine, the ratio of the area under the curve of the free drug plasma concentration to the minimum inhibitory concentration (MIC) (fAUC/MIC) and the time that free plasma concentration exceeds the MIC over the dosing interval (fT > MIC). The basic concepts of PK/PD modelling of AMDs were established some 20 years ago. Earlier studies have been reviewed previously and are not reconsidered in this review. This review describes and provides a critical appraisal of more recent, advanced PK/PD approaches, with particular reference to their application in veterinary medicine. Also discussed are some hypotheses and new areas for future developments. First, a brief overview of PK/PD principles is presented as the basis for then reviewing more advanced mecha-nistic considerations on the precise nature of selected indices. Then, several new approaches to selecting PK/PD indices and establishing their numerical values are reviewed, including (a) the modelling of time-kill curves and (b) the use of population PK investigations. PK/PD indices can be used for dose determination, and they are required to establish clinical breakpoints for antimicrobial susceptibility testing. A particular consideration is given to the precise nature of MIC, because it is pivotal in establishing PK/PD indices, explaining that it is not a "pharmacodynamic parameter" in the usual sense of this term. K E Y W O R D S antimicrobials, dosage regimen, PK/PD, veterinary medicine
This study aimed to assess antimicrobial susceptibility of members of the family Flavobacteriaceae isolated from Nile tilapia (Oreochromis niloticus). Antimicrobial susceptibility of 67 Flavobacteriaceae isolates originating mainly from ponds and Lake Victoria against 19 antimicrobial agents was determined by the broth micro dilution method. Overall, most isolates were susceptible to enrofloxacin (97%; MIC 90 2 μg/ml) followed by novobiocin (85%, MIC 90, 4 μg/ml) and the aminoglycoside streptomycin (85%; MIC 90 , 128 μg/ml). Some isolates were also susceptible towards trimethoprim/sulfamethoxazole (77.6%), neomycin and florfenicol both at 62.7%. Susceptibility levels were low for tylosin tartrate (32.8%), clindamycin and sulphathiazole both at (23.9%), ceftiofur (6%), spectinomycin (6%) and tetracyclines/oxtetracyclines (4.5%). In contrast, β-Lactams (amoxicillin, penicillin), gentamycin and erythromycin exhibited very poor activity against Flavobacteriaceae isolates. The extent of antimicrobial susceptibility did not vary significantly among isolates from farmed and wild fish isolates (P > 0.01). The highest Multiple Antimicrobial Resistance (MAR) index was observed in Chryseobacterium indologenes (0.89) and the lowest in Chaetoderma indicum isolates (0.32). Our results indicate that most of Flavobacteriaceae isolates are multidrug resistance, and this may be associated with intrinsic resistance mechanisms to a broad range of antimicrobial agents. However, the need remains to carryout in-depth study to understand better the underlying genetic mechanisms given that the magnitude and trend for susceptibility was comparable between isolates from aquaculture and fisheries. The findings from this study give us insight into appropriate choice of antimicrobial agents for effective treatment of infections caused by these isolates.
VetCAST is the EUCAST sub-committee for Veterinary Antimicrobial Susceptibility Testing. Its remit is to define clinical breakpoints (CBPs) for antimicrobial drugs (AMDs) used in veterinary medicine in Europe. This position paper outlines the procedures and reviews scientific options to solve challenges for the determination of specific CBPs for animal species, drug substances and disease conditions. VetCAST will adopt EUCAST approaches: the initial step will be data assessment; then procedures for decisions on the CBP; and finally the release of recommendations for CBP implementation. The principal challenges anticipated by VetCAST are those associated with the differing modalities of AMD administration, including mass medication, specific long-acting product formulations or local administration. Specific challenges comprise mastitis treatment in dairy cattle, the range of species and within species breed considerations and several other variable factors not relevant to human medicine. Each CBP will be based on consideration of: (i) an epidemiological cut-off value (ECOFF) – the highest MIC that defines the upper end of the wild-type MIC distribution; (ii) a PK/PD breakpoint obtained from pre-clinical pharmacokinetic data [this PK/PD break-point is the highest possible MIC for which a given percentage of animals in the target population achieves a critical value for the selected PK/PD index (fAUC/MIC or fT > MIC)] and (iii) when possible, a clinical cut-off, that is the relationship between MIC and clinical cure. For the latter, VetCAST acknowledges the paucity of such data in veterinary medicine. When a CBP cannot be established, VetCAST will recommend use of ECOFF as surrogate. For decision steps, VetCAST will follow EUCAST procedures involving transparency, consensus and independence. VetCAST will ensure freely available dissemination of information, concerning standards, guidelines, ECOFF, PK/PD breakpoints, CBPs and other relevant information for AST implementation. Finally, after establishing a CBP, VetCAST will promulgate expert comments and/or recommendations associated with CBPs to facilitate their sound implementation in a clinical setting.
The pharmacokinetics of enrofloxacin (ENR) was studied in crucian carp (Carassius auratus gibelio) after single administration by intramuscular (IM) injection and oral gavage (PO) at a dose of 10 mg/kg body weight and by 5 mg/L bath for 5 hr at 25°C. The plasma concentrations of ENR and ciprofloxacin (CIP) were determined by HPLC. Pharmacokinetic parameters were calculated based on mean ENR or CIP concentrations using WinNonlin 6.1 software. After IM, PO and bath administration, the maximum plasma concentration (Cmax ) of 2.29, 3.24 and 0.36 μg/ml was obtained at 4.08, 0.68 and 0 hr, respectively; the elimination half-life (T1/2β ) was 80.95, 62.17 and 61.15 hr, respectively; the area under the concentration-time curve (AUC) values were 223.46, 162.72 and 14.91 μg hr/ml, respectively. CIP, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration except bath. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the crucian carp using IM, PO and bath immersion administration.
This review outlines the current knowledge on the use of enrofloxacin in veterinary medicine from biochemical mechanisms to the use in the field conditions and even resistance and ecotoxicity. The basics of biochemistry, the mechanisms of action and resistance and pharmacokinetics are presented. Then an overview of available veterinary products, their efficacy and their toxicity against target species, human and environment is provided.
The objective of this study was to evaluate the disposition kinetics of enrofloxacin (ENR) in the plasma and its distribution in the muscle tissue of Nile tilapia (Oreochromis niloticus) after a single oral dose of 10 mg/kg body weight via medicated feed. The fish were kept at a temperature between 28 and 30 °C. The collection period was between 30 min and 120 h after administration of the drug. The samples were analyzed by high-performance liquid chromatography with a fluorescence detector (HPLC-FLD). The ENR was slowly absorbed and eliminated from the plasma (Cmax = 1.24 ± 0.37 μg/mL; Tmax = 8 h; T1/2Ke = 19.36 h). ENR was efficiently distributed in the muscle tissue and reached maximum values (2.17 ± 0.74 μg/g) after 8 h. Its metabolite, ciprofloxacin (CIP), was detected and quantified in the plasma (0.004 ± 0.005 μg/mL) and muscle (0.01 ± 0.011 μg/g) for up to 48 h. After oral administration, the mean concentration of ENR in the plasma was well above the minimum inhibitory concentrations (MIC50 ) for most bacteria already isolated from fish except for Streptococcus spp. This way the dose used in this study allowed for concentrations in the blood to treat the diseases of tilapia.
© 2015 John Wiley & Sons Ltd.
Twenty one Aeromonas isolates pathogenic for carp were tested for susceptibility to 22 antimicrobial agents. Of the all isolates examined, 100% were resistant to ampicillin and penicillin, and sensitive to trimethoprim-sulphamides, oxolinic acid, flumequine, chloramphenicol, norfloxacin, linkomycin, pefloxacin. Most isolates were resistant to cephalothin (57%) and erythromycin (52%). The minimal inhibitory concentrations (MICs) of seven antimicrobials agents (chloramphenicol, enrofloxacin, flumequine, nalidixic acid, norfloxacin, oxolinic acid and oxytetracycline) were determined for A. hydrophila (n=18) and A. sobria (n=3). MICs were determined using an agar dilution technique in Mueller-Hinton medium. The MICs of each antimicrobial for each isolate examined, together with the minimum concentrations of each antimicrobial required to inhibit 50% (MIC 50) and 90% (MIC 90) of the isolates examined, were also determined. The more recently synthetized 4-quinolones showed very good activity against all isolates examined compared with lower activity of oxytetracycline. The enrofloxacin was the most active (MIC 90 = 0.25 mg L -1).
The aim of the study was to investigate the serum and tissue disposition of enrofloxacin and its active metabolite ciprofloxacin in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus caprio) after single oral administration at a dose of 10 mg/kg. Concentrations of enrofloxacin in the serum of rainbow trout showed high variability with two peaks at the 3(rd) and 24th hour after administration. The highest concentrations were found in the liver. The curves of liver levels showed similar changes to the respective serum samples. In the muscles, enrofloxacin concentrations were also higher compared to the respective serum samples. Ciprofloxacin concentrations were lower and showed smaller variations in all investigated tissues. The serum and tissue concentrations of enrofloxacin and ciprofloxacin in common carp showed two peaks, with the first Cmax at the 3rd hour after drug administration as in rainbow trout. Concentrations of both investigated substances were higher in the liver than in the serum. The differences in common carp were less pronounced in comparison to rainbow trout. Relatively high levels of both substances were found in the muscles. Seven days after treatment enrofloxacin concentrations in the serum and tissues were within the therapeutic levels for most of the sensitive microorganisms in trout. Lower concentrations of its metabolite ciprofloxacin were found in the investigated tissues at the last sampling point. Lower levels of both substances were found in carp.
Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain.
The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 mug/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 mug enrofloxacin per g body weight. Dosing of 30 mug/g resulted in serum maximum concentration (Cmax) of 7.151 mug/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 mug/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.
Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.
The pharmacokinetics of intravenously and orally administered enrofloxacin was determined in fingerling rainbow trout (Oncorhymhur mykiss). Doses of 5 or 10 mg enrofloxacin /kg body weight were administered intravenously to 26 fish for each dose and blood was sampled over a 60-h period at 15°C. Two groups of fish were treated orally with 5, 10, or 50 mg/kg (80 fish/dose at each temperature) and held at 15°C or 10°C during the 60-h sampling period. Following intravenous administration, the serum concentration—time data of enrofloxacin in rainbow trout were best described by a two-compartment open model for both doses of 5 and 10 mg enrofloxacin/kg. The hybrid rate constants a and β did not differ between doses. The distributional phase was rapid with a half-life of 6–7 min for both doses. Overall half-lives of elimination were 24.4 h (95% CI = 20.2–30.8) and 30.4 h (24.241.0), respectively, for the 5– and 10-mg/ kg doses. A large Vd(area) was observed following dosing of either 5 or 10 mg enrofloxacin/kg,: 3.22 and 2.56 l/kg, respectively. Whole body clearance for 5 mg/kg was 92 ml/h.kg and 58 ml/h-kg at the 10-mg/kg dose. Following oral administration, the serum concentration—time data for enrofloxacin were best described as a one-compartment open model with first-order absorption and elimination. Apparent Ka over all doses at 10°C averaged 62% less than apparent Ka, at 15°C. Estimates of the apparent t(1/2)e over both temperatures ranged from 29.5 h (18.4–73.4) to 56.3 h (38.3–106.6). Bioavailability averaged 42% over all doses at 15°C and was decreased to an average of 25% at 10°C. Peak serum concentrations appeared between 6 and 8 h following dosing. A dose of 5 mg/kg/ day was estimated to provide average steady-state serum concentrations at 10°C that are approximately 4.5 times the highest reported MIC values for Streptococcus spp., the fish pathogen least sensitive to enrofloxacin. Owing to the long apparent half-life of elimination of enrofloxacin in fingerling trout, it would take approximately 5 to 9 days to achieve these predicted steady-state serum concentrations; this estimate is important when considering the duration of therapy in clinical trials.
The aim of this study was to determine antimicrobial resistance of Aeromonas hydrophila isolated from farmed Nile Tilapia. A total of 50 A. hydrophila isolates from clinical cases were screened for the presence of class 1, 2 and 3 integrons and all the strains resistant to enrofloxacin and/or ciprofloxacin (n=19) examined for mutation in the quinolone resistance-determining regions (QRDRs) of gyrA and parC. The intI1 gene was detected in 23 A. hydrophila strains (46%) but no intl2 and intl3 were detected. Among these, 14 isolates (60.8%) carried gene cassettes inserted in variable regions i.e., partial aadA2, aadA2, dfrA1-orfC and dfrA12-aadA2, of which the most common gene cassette array was dfrA12-aadA2 (26.09%). Conjugal transfer of class 1 integrons with resistance gene array was detected. All the A. hydrophila strains resistant to enrofloxacin and/or ciprofloxacin possessed mutations in the QRDRs of gyrA and parC. Only a Ser-83-Ile substitution was identified in GyrA and only a Ser-80-Ile amino change was found in ParC. The data confirms that A. hydrophila from farm-raised Nile Telapia serve as a reservoir for antimicrobial resistance determinants.
The in vitro antimicrobial activities of oxolinic acid, flumequine, sarafloxacin, enrofloxacin, and oxytetracycline against strains of bacteria pathogenic to fish (Aeromonas salmonicida subsp. salmonicida, atypical A. salmonicida, Vibrio salmonicida, Vibrio anguillarum, and Yersinia ruckeri) were determined at two different incubation temperatures, 4 and 15 degrees C, by a drug microdilution method. The main objective of the study was to examine the effect of incubation temperature on the in vitro activities of 4-quinolones and oxytetracycline against these bacteria. When tested against A. salmonicida subsp. salmonicida, all of the quinolones examined had MICs two- to threefold higher at 4 degrees C than at 15 degrees C. Similarly, 1.5- to 2-fold higher MICs were recorded for all of the quinolones except sarafloxacin at 4 degrees C than at 15 degrees C when the drugs were tested against V. salmonicida. In contrast to those of the quinolones, the MICs of oxytetracycline were two- to eightfold lower at 4 degrees C than at 15 degrees C against all of the bacterial species tested. Of the antimicrobial agents tested against the bacterial species included in the study, enrofloxacin was the most active and oxytetracycline was the least active. Sarafloxacin was slightly more active than flumequine and oxolinic acid, especially against oxolinic acid-resistant A. salmonicida subsp. salmonicida strains.
Quinolones are currently the most commonly used group of antimicrobial agents in Norwegian aquaculture. The aims of this study were to examine and compare the pharmacokinetic properties of the quinolones oxolinic acid, flumequine, sarafloxacin, and enrofloxacin after intravascular and oral administration to Atlantic salmon (Salmo salar) by using identical experimental designs. The study was performed in seawater at 10.2 +/- 0.2 degree C with Atlantic salmon weighing 240 +/- 50 g (mean +/- standard deviation). The bioavailability varied considerably among the four quinolones. Following oral administration of medicated feed, the bioavailabilities of oxolinic acid, flumequine, sarafloxacin, and enrofloxacin were 30.1, 44.7, 2.2, and 55.5%, respectively. Taking the different dosages (25 mg/kg of body weight for oxolinic acid and flumequine and 10 mg/kg for sarafloxacin and enrofloxacin) into account, enrofloxacin showed the highest maximum concentration in plasma, followed by flumequine, oxolinic acid, and sarafloxacin. Following intravenous administration, the volumes of distribution at steady state of oxolinic acid, flumequine, sarafloxacin, and enrofloxacin were 5.4, 3.5, 2.3, and 6.1 liters/kg, respectively. Hence, all the quinolones showed good tissue penetration in Atlantic salmon. The elimination half-life of three of the quinolones, oxolinic acid, flumequine, and sarafloxacin, was less than or equal to 24 h, with oxolinic acid showing the shortest (18.2 h). On the other hand, the elimination half-life of enrofloxacin was estimated to be 34.2 h, almost twice that of oxolinic acid. This study showed that flumequine and enrofloxacin had better pharmacokinetic properties, compared with those of oxolinic acid, in Atlantic salmon held in seawater.
The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu. The half-life for enrofloxacin following i.m. administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises. The 4 h maximum concentration (Cmax) of 1.64 micrograms/ml, following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish. At 48 h post i.m. administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens. The gavage method of oral enrofloxacin administration produced a Cmax of 0.94 microgram/mL at 6-8 h. This Cmax was well above the reported in vitro MIC. A bath immersion concentration of 2.5 mg/L for 5 h was used in this study. The Cmax of 0.17 microgram/mL was noted on the 2 hour post-treatment plasma sample. Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded. Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration. The i.m. route is the most predictable and results in the highest plasma concentrations of the drug.
This study aimed to determine the pharmacokinetics and bioavailability of cefquinome in rainbow trout (Oncorhynchus mykiss) following intravascular (IV), intraperitoneal (IP), and oral (PO) administrations at 14 ± 1°C. In this study, three hundred and six clinically healthy rainbow trout (110–140 g) were used. The fish received single IV, IP, and PO injections of cefquinome at 10 mg/kg dose. The plasma concentrations of cefquinome were measured using HPLC‐UV and were evaluated using non‐compartmental analysis. Cefquinome was measured up to 96 h for PO route and 144 h for IV and IP routes in plasma. Following IV administration, t1/2ʎz, ClT, and Vdss were 18.85 h, 0.037 L/h/kg, and 0.84 L/kg, respectively. The Cmax of IP and PO routes was 9.75 and 1.64 μg/ml, respectively. The bioavailability following IP and PO administrations was 59.46% and 12.33%, respectively. Cefquinome at 10 mg/kg dose may maintain T > MIC above 40% at 72 and 96 h intervals, respectively, following the IP and IV routes for bacteria with MIC values of ≤2 μg/ml and at 24 h intervals following the PO route for bacteria with MIC value of ≤0.75 μg/ml. However, further studies are needed to determine in vitro and in vivo antibacterial efficacy and multiple dosage regimens of cefquinome against pathogens isolated from rainbow trout.
The present study was designed to explore pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in healthy and Vibrio alginolyticus-infected large yellow croaker (Pseudosciaena crocea) after a single 10 mg/kg oral dose. Concentrations of enrofloxacin and ciprofloxacin in serum, liver, kidney, muscle and skin of fish were determined using high-performance liquid chromatography. Pharmacokinetic parameters were analysed based on classical compartmental model analysis. The overall changes in enrofloxacin concentration–time curves in serum and tissues of diseased fish were similar to those of healthy fish. However, the peak concentration and peak time of enrofloxacin in serum and tissues were different in healthy and diseased fish. A delay of enrofloxacin peak time in serum and all tissues appeared in the diseased fish. The peak concentrations in serum and tissues of the diseased fish were lower than those of healthy fish. In healthy fish, the area under the concentration–time curve (AUC) was in the order serum >liver > kidney >muscle > skin, while AUC was serum >live > muscle >kidney > skin in the diseased fish. The peak concentrations of ciprofloxacin in the liver, serum, kidney, muscle and skin of healthy fish were 0.93 μg/g, 0.55 μg/ml, 0.36 μg/g, 0.37 μg/g and 0.12 μg/g respectively. Tmax of ciprofloxacin in the corresponding tissues was 8, 24, 12, 12 and 16 h respectively. In the diseased fish, the peak concentrations of ciprofloxacin in the corresponding tissues were 0.52 μg/g, 0.52 μg/ml, 0.41 μg/g, 0.27 μg/g and 0.13 μg/g respectively. Tmax in the corresponding tissues were 0.5, 8, 12, 16 and 48 h respectively. These data indicate that the health status of fish affects drug absorption and metabolism.
This book contains 12 chapters that discuss the history, current state and future of tilapia ( Oreochromis and Tilapia spp.); basic biology and ecology; environmental requirements; semi-intensive fish culture; intensive culture; nutrition and feeding; reproduction and seed production; stress and diseases; harvesting, processing and production economics; the role of tilapia culture in rural development; modern technologies in reproduction and genetics (including cloning and transgenesis) and the environmental impacts of tilapia culture and the best management methods to reduce those impacts. This book is intended for those with an interest in aquaculture in general or to those involved in tilapia culture in particular.
Enrofloxacin is a fluoroquinolone antimicrobial agent used in freshwater rainbow trout against the main pathogenic bacteria Aeromonas salmonicida, Yersinia ruckeri and Flavobacterium psychrophilum. However, the current “standard” dose (10 mg/kg/day for 10 days) was based only on some old, rather limited experimental data, and needed to be re-assessed. Thus, a pharmacokinetic-pharmacodynamic (PKPD) approach was used by combining a population PK model with new epidemiological data (Minimum Inhibitory Concentrations (MIC)) of the three bacterial species to determine optimal enrofloxacin doses in rainbow trout.
Ninety-six rainbow trout (half diploid, half triploid) were randomly assigned to four different groups and received oral (gavage) and then intravenous administration of enrofloxacin at four different doses (range 5–60 mg/kg). Individual blood samples were taken to develop a population PK model.
Enrofloxacin should be considered as a long-acting drug in trout due to the observed long plasma half-life (>100 h), which is therefore inadequate with the “standard” dosage based on daily oral administrations. Moreover, the fish ploidy had an impact on the PK of enrofloxacin with a longer persistence of enrofloxacin in triploid individuals, which raises the question of the withdrawal period to apply. The absolute bioavailability of oral enrofloxacin was estimated at ~88%.
For F. psychrophilum, the provisional epidemiological cut-off value (CONRI), calculated according to the NRI method, was equal to 0.03 μg/mL. For A. salmonicida and Y. ruckeri, however, no clear bimodal distribution of MIC could be observed, and therefore no relevant CONRI could be obtained.
According to our model, a single oral dose of ~5 mg/kg should provide sufficient exposure to treat the wild-type population of F. psychrophilum for 4 days, while complying with the PKPD breakpoints. Then, a maintenance dose of ~2.5 mg/kg could possibly be re-administered every 4 days. The absence of a CONRI did not allow to predict an optimal dose for the two other bacteria. As more than 70% of A. salmonicida isolates in our data set have an enrofloxacin MIC ≥0.25 μg/mL, it seems that enrofloxacin should not be recommended against this bacterium.
The PKPD approach allowed us to refine the dosing regimens in rainbow trout, for a more sustainable approach. These new dosing regimens have yet to be clinically confirmed.
Enrofloxacin (ENR) is effective in the prevention and treatment of bacterial infections caused by various fish pathogenic bacteria such as Aeromonas spp., Vibrio spp., Nocardia and Yersinia spp. The purpose of this work was to explore the pharmacokinetics (PK), tissue distribution, and depletion of ENR and its main metabolite, ciprofloxacin (CIP), in northern snakehead (Channa argus) reared at 25 °C during and after repeated oral dose of 10 mg/kg animal body weight per day for a total of 5 days. ENR and CIP concentrations were simultaneously determined in the plasma, liver, kidney, gill, and muscle with adhering skin by HPLC with fluorescence detection. Using a non-compartmental analysis, PK parameters were derived from the mean concentration versus time data of ENR and CIP. The results showed a slow absorption, long half-life and wide tissue distribution of ENR in the northern snakehead. The maximum concentrations of ENR in the plasma, muscle plus skin, liver, kidney, and gill tissues were observed at 3, 6, 6, 6, and 9 h post treatment, respectively, and the corresponding depletion half-lives (T1/2z) were 78.00, 83.24, 82.56, 126.07, and 68.70 h, respectively. The extent of ENR distribution into the tissues followed the decreasing order of liver > kidney > gill > plasma > muscle plus skin. The highest concentrations of both ENR and CIP were observed in the liver, suggesting that liver is the major site of ENR metabolism in northern snakehead. The Cmax/MIC and AUC24/MIC ratios obtained in the present study indicated that the ENR regimen employed would be effective in treatment of infections caused by susceptible strains with MIC values below 0.7 μg/mL. Based on the calculation results, a reasonable withdrawal period should not be less than 18 days at 25 °C for ENR in northern snakehead after treatment ceased.
• Plasma pharmacokinetics and tissue disposition of enrofloxacin was studied in rainbow trout (Oncorhynchus mykiss) after a single oral administration of 10mg/kg, and by immersion baths of 20 ppm during 2.5 hours and 100 ppm during 0.5 hours, at water temperature of 16.3 ± 0.3 °C.
• Concentrations of enrofloxacin in plasma and tissues (skin, muscle, liver, kidney and gut) were determined using high performance liquid chromatography (HPLC) with fluorescence detection.
• Pharmacokinetic parameters were analysed with a non-compartmental model. After oral administration, t½β, AUC and AUCtissues/AUCplasma ratio were 42.98 h, 21.80 μg-h/mL and ≤18.63, respectively.
• After immersion baths of 20 ppm during 2.5 hours and 100 ppm during 0.5 hours, the t½β, AUC and AUCtissues/AUCplasma were 42.77 and 44.67, 9.83 and 12.83 μg-h/mL and ≤9.81 and ≤7.13, respectively.
• Therefore, oral (10 mg/kg) and bath administration in rainbow trout can provide AUC/MIC of ≥125 and Cmax/MIC of ≥10 to treat diseases caused by susceptible bacteria with MIC ≤0.04 μg/ml. This information can be helpful for the right use of enrofloxacin in rainbow trout. Also, this is the first study that determines the antibiotic tissue disposition in rainbow trout by using different administration routes.
The pharmaco-kinetic/dynamic of marbofloxacin was investigated after single intravenous (IV) and oral administration of 10 mg/kg in 192 healthy rainbow trout at 13±1.2 oC. The plasma concentrations of marbofloxacin were determined by high-performance liquid chromatography-ultraviolet detection. After IV and oral administration, the plasma concentration–time data were described by a noncompartmental analysis. The minimal inhibitory concentration (MIC) of marbofloxacin against Yersinia ruckeri, Aeromonas hydrophila, Pseudomonas fluorescens and P. putida were determined by broth dilution method at 13 oC. After IV administration, the elimination half-life (t1/2ʎz), area under the concentration-versus time curve (AUC0-∞), apparent volume of distribution at steady-state and total body clearance of marbofloxacin were 18.05 h, 354.63 h*μg/mL, 0.65 L/kg and 0.03 L/h/kg, respectively. After oral administration, t1/2ʎz, AUC0-∞, the peak plasma concentration, time of maximum concentration and bioavailability were 27.51 h, 135.29 h*μg/mL, 3.74 μg/mL, 4 h and 38.15%, respectively. The respective MICs of marbofloxacin against Y. ruckeri, A. hydrophila, P. fluorescens and P. putida were determined as 0.02 μg/mL, 2.5 μg/mL, 2.5 μg/mL and 5 μg/mL, respectively. Following IV and oral administration of 10 mg/kg marbofloxacin, AUC/MIC and Cmax/MIC values were above the target levels for Y. ruckeri, while this dose was not sufficient for A. hydrophila and Pseudomonas spp. Because the pharmacokinetics and pharmacodynamics of a drug in fish are significantly affected by temperature, the dosage regimen of marbofloxacin should be modified according to temperature.
The study was carried out to evaluate the pharmacokinetic disposition of enrofloxacin (ENF) with a single dose of 20 mg/kg after oral administration in largemouth bass (Micropterus salmoides) at 28°C. The concentrations of ENF and of its metabolite ciprofloxacin (CIP) in plasma, liver, and muscle plus skin in natural proportions were determined using HPLC. The concentration–time data for ENF in plasma were best described by a two‐compartment open model. After oral administration, the maximum ENF concentration (Cmax) of 10.99 μg/ml was obtained at 0.60 hr. The absorption half‐life (T1/2Ka) of ENF was calculated to be 0.07 hr whereas the elimination half‐life (T1/2β) of the drug was 90.79 hr. The estimates of area under the plasma concentration–time curve (AUC) and apparent volume of distribution (Vd/F) were 1,185.73 μg hr/ml and 2.21 L/kg, respectively. ENF residues were slowly depleted from the liver and muscle plus skin of largemouth bass with the T1/2β of 124.73 and 115.14 hr, respectively. Very low levels of ciprofloxacin were detected in the plasma and tissues. A withdrawal time of 24 days was necessary to ensure that the residues of ENF + CIP in muscle plus skin were less than the maximal residue limit (MRL) of 100 μg/kg established by the European Union.
The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty‐four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half‐life (t1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr−1 kg−1, respectively. The PK parameters of ENR and DNX following IM injection were t1/2λz 21.10 and 28.41 hr, AUC0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC0‐48CPR/AUC0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC0‐24/minimum inhibitory concentration (MIC) and maximum concentration (Cmax)/MIC ratios for susceptible bacteria, with the MIC90 of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.
Plasma and muscle pharmacokinetics of danofloxacin were investigated after 10 mg/kg intravenous (IV, caudal vein) and intramuscular (IM, right epaxial muscles) administrations in 168 healthy brown trout (Salmo trutta fario) at 10°C–13°C. High-performance liquid chromatography was used to determine its plasma and muscle concentrations. Pharmacokinetic parameters were analysed with a non-compartmental model. After IV administration, elimination half-life (t1/2ʎz), area under the concentration–time curve (AUC0–∞), mean residence time (MRT0–∞), volume of distribution at steady state, total body clearance in plasma and AUCMuscle/AUCPlasma ratio were 22.22 h, 140.66 h*µg/mL, 23.15 h, 2.28 L/kg, 0.07 L/h/kg and 3.79, respectively. After IM administration, t1/2ʎz, AUC0–∞, MRT0–∞, peak concentration (Cmax), time to reach Cmax, bioavailability in plasma and AUCMuscle/AUCPlasma ratio were 28.28 h, 84.39 h*µg/mL, 37.31 h, 4.79 µg/mL, 1 h, 59.99% and 8.46, respectively. Danofloxacin exhibited long t1/2ʎz and good bioavailability after IM administration. Therefore, 10 mg/kg IM administration of danofloxacin in brown trout can provide AUC0–24/MIC of > 125 and Cmax/MIC of > 10 to treat diseases caused by susceptible bacteria with ≤ 0.336 µg/mL MIC.
Ceftriaxone (CTX) is a third-generation cephalosporin that has proven to be effective in the treatment of infections caused by a wide range of gram- positive and gram-negative microorganisms. This study aimed to determine the plasma and muscle pharmacokinetics of CTX after its administration via the intravenous (IV) and intramuscular (IM) routes to brown trout (Salmo trutta fario) at temperatures of 10°C–13°C. In total, 140 healthy brown trout (body weight, 245 ± 38 g) were used. The brown trout received single IV and IM injections of CTX at 25 mg/kg. The IV doses were injected into the caudal vein, whereas the IM doses were injected into the right epaxial muscles. The plasma and muscle tissue concentrations of CTX were measured using high- performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental methods. Following the IV administration of CTX, the elimination half-life (t1/2ʎz), volume of distribution at steady state, total body clearance, and area under the concentration–time curve (AUC0–72) in plasma were 5.83 h, 0.09 L/kg, 0.02 L/h/kg, and 1079.46 h*μg/mL, respectively. After the IM administration of CTX, plasma t1/2ʎz, peak plasma concentration (Cmax), time to reach Cmax, and bioavailability were 22.78 h, 87.92 μg/mL, 0.5 h, and 27.19%, respectively. The AUCMuscle/AUCPlasma ratio following the IV administration was 0.02 and that following the IM administration was 0.04. CTX exhibited low bioavailability and prolonged t1/2ʎz after the IM administration. The prolonged t1/2ʎz of CTX could thus be beneficial in brown trout. Nevertheless, future studies that aim to determine the clinical efficacy and pharmacokinetics after repeated administration of CTX are warranted.
Biotransformation may substantially impact the toxicity and accumulation of xenobiotic chemicals in fish. However, this activity can vary substantially within and among species. In this study, liver S9 fractions from rainbow trout (4-400 g) were used to evaluate relationships between fish body mass and the activities of phase I and phase II metabolic enzymes. An analysis of log-transformed data expressed per gram of liver (g liver-1) showed that total cytochrome P450 (CYP) concentration, UDP-glucuronosyltransferase (UGT) activity, and glutathione S-transferase (GST) activity exhibited small but significant inverse relationships with fish body weight. In contrast, in vitro intrinsic clearance rates (CLIN VITRO,INT; mL min-1 mg protein-1) for three polycyclic aromatic hydrocarbons (PAHs) increased with increasing body weight. Weight normalized liver mass also decreased inversely with body weight, suggesting a need to express hepatic metabolism data per gram of body weight (g BW-1) in order to reflect the metabolic capabilities of the whole animal. When the data were recalculated in this manner, negative allometric relationships for CYP concentration, UGT activity, and GST activity became more pronounced, while CLIN VITRO,INT rates for the three PAHs showed no significant differences across fish sizes. Ethoxyresorufin O-deethylase (EROD) activity normalized to tissue weight (g liver-1) or body weight (g BW-1) exhibited a non-monotonic pattern with respect to body weight. The results of this study may have important implications for chemical modeling efforts with fish.
The pharmacokinetic (PK) properties of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in crucian carp following oral administration at different dose levels (5, 10, 20, 40 mg/kg body weight). The disposition kinetics of ENR was found to be linear over the dose range studied. Serum half‐lives ranged from 64.56 to 72.68 hr. The in vitro and ex vivo activities of ENR in serum against a pathogenic strain of Aeromonas hydrophila were determined. In vitro and ex vivo bactericidal activity of ENR was concentration dependent. Dosing of 10 mg/kg resulted in an AUC/minimum inhibitory concentration (MIC) ratio of 368.92 hr and a Cmax/MIC ratio of 7.23, respectively, against A. hydrophila 147 (MIC = 0.48 μg/ml), indicating a likely high level of effectiveness in clinical infections caused by A. hydrophila with MIC value ≤ 0.48 μg/ml. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided the values of AUC24 hr/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria, these values were 21.70, 53.01, and 125.21 hr, respectively. These findings in conjunction with MIC90 data suggested that ENR at the dose of 7.81 mg/kg predicted a positive clinical outcome and minimize the risk of emergence of resistance.
The organization of the gastrointestinal (GI) tract of fish follows the basic features as in other vertebrate groups with a degree of variation in phylogeny and ontogeny, feeding habits, diet, nutrition, physiological conditions and the special functions the gut may perform. There are enormous variations in the morphology of the GI tract among various fish species. The variations in the organization of the GI tract ensure optimum utilization of dietary nutrients, which in many cases means efficient primary digestion and a large intestinal absorptive surface area. Different fish species have adapted different approaches to accommodate this objective. Of particular interest to fish nutritionists is the comparison of morphological features in relation to natural diets. In order to compare data obtained from one fish species with other species, it is essential to make divisions into a broad line of common morphological features.
The present study was designed to explore the pharmacokinetics of enrofloxacin in Takifugu flavidus at different salinity levels (10‰, 20‰ and 30‰). The concentrations of enrofloxacin in plasma and tissues (kidney, liver and muscle) of T. flavidus after a single oral dose of 10 mg kg−1 were simultaneously determined using HPLC. The parameters of pharmacokinetics were calculated using non-compartmental model based on statistic moment theory. The peak concentrations of enrofloxacin were higher and Tmax values in plasma, liver and muscle tissues of T. flavidus were lower at the salinity of 20‰ and 30‰ than that of 10‰, except the kidney tissue. These demonstrated the absorption of enrofloxacin was more quickly and more quantity at the high salinity. The elimination half-life (t1/2z) of enrofloxacin in the plasma (45.22, 69.91 and 95.45 h) was increasing with the increase in salinity. And the t1/2z values of enrofloxacin in liver (76.44, 44.21 and 33.48 h) and kidney (212.16, 157.43 and 35.61 h) both decline with the increase in salinity, indicating the elimination of enrofloxacin was faster in liver and kidney but slower in plasma at the high salinity. The content of enrofloxacin in liver was increasing with the increase in salinity, suggesting that salinity affects tissue distribution and metabolism in T. flavidus. In addition, the AUC0–∞ data of enrofloxacin (kidney > plasma > liver > muscle) at different salinity levels were essentially consistent, and AUC0–∞ data of kidney were declined with the increase in salinity, supporting that the kidney was the main organ and the role of extent of kidney on excretion was different in different salinity levels.
The comparative pharmacokinetics of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in healthy and Aeromonas hydrophila-infected crucian carp after a single oral (p.o.) administration at a dose of 10 mg/kg at 25 °C. The plasma concentrations of ENR and of CIP were determined by HPLC. Pharmacokinetic parameters were calculated based on mean ENR concentrations by noncompartmental modeling. In healthy fish, the elimination half-life (T1/2λz), maximum plasma concentration (Cmax), time to peak (Tmax), and area under the concentration–time curve (AUC) values were 64.66 h, 3.55 μg/mL, 0.5 h, and 163.04 μg·h/mL, respectively. In infected carp, by contrast, the corresponding values were 73.70 h, 2.66 μg/mL, 0.75 h, and 137.43 μg·h/mL, and the absorption and elimination of ENR were slower following oral administration. Very low levels of CIP were detected, which indicates a low extent of deethylation of ENR in crucian carp.
Health maintenance Stress Hazard reduction by management Location, soil, and water Avoiding exposure Exposing dose Extent of contact Protection by segregation Problem of new arrivals Breeding and culling Nutritional basis of health maintenance Eradication, prevention, control Variable causes require variable solutions Don't just cure, prevent Law of limiting factors Staying on top of the operation Early diagnosis A dynamic team effort Keeping current Maintaining a clean environment High-risk concept Record keeping and Fish health status References
The pharmacokinetics of enrofloxacin (EF) was investigated after single intravenous (i.v.) and oral (p.o.) dose of 10 mg/kg body weight (b.w.) in snakehead fish at 24-26 °C. The plasma concentrations of EF and its metabolite ciprofloxacin (CF) were determined by high-performance liquid chromatography. The plasma concentration-time data were described by an open two-compartment model for both routes. After intravenous administration, the elimination half-life (T1/2β ), area under the concentration-time curve (AUC) and total body clearance of EF were 19.82 h, 75.79 μg h/mL and 0.13 L/h/kg, respectively. Following p.o. administration, the maximum plasma concentration (Cmax ), T1/2β and AUC of EF were 1.86 μg/mL, 35.8 h and 49.98 μg h/mL, respectively. Absorption of EF was good with a bioavailability (F) of 65.82%, which was higher than that calculated in most seawater fish. CF, an active metabolite of EF, was detected occasionally in this study, which indicates a low extent of deethylation of EF in snakehead fish.
Aquaculture has become an important source of fish available for human consumption. In order to achieve greater productivity, intensive fish cultivation systems are employed, which can cause greater susceptibility to diseases caused by viruses, bacteria, fungi, and parasites. Antimicrobial substances are compounds used in livestock production with the objectives of inhibiting the growth of microorganisms and treatment or prevention of diseases. It is well recognized that the issues of antimicrobial use in food animals are of global concern about its impact on food safety. This paper present an overview of the aquaculture production in the whole world, raising the particularities in Brazil, highlighting the importance of the use of veterinary drugs in this system of animal food production, and address the potential risks arising from their indiscriminate use and their impacts on aquaculture production as they affect human health and the environment. The manuscript also discusses the analytical methods commonly used in the determination of veterinary drug residues in fish, with special issue for fluroquinolones residues and with emphasis on employment of LC-MS/MS analytical technique.
Health Maintenance and Principal Microbial Diseases of Cultured Fishes, Third Edition is a thoroughly revised and updated version of the classic text. Building on the wealth of information presented in the previous edition, this new edition offers a major revision of the valuable health maintenance section, with new pathogens added throughout the book. Health Maintenance and Principal Microbial Diseases of Cultured Fishes, Third Edition focuses on maintaining fish health, illustrating how management can reduce the effects of disease. The text is divided into sections on health maintenance, viral diseases, and bacterial diseases, and covers a wide variety of commercially important species, including catfish, salmon, trout, sturgeon, and tilapia. This book is a valuable resource for professionals and students in the areas of aquaculture, aquatic health maintenance, pathobiology, and aquatic farm management.
Defining the pharmacokinetic parameters and depletion intervals for antimicrobials used in fish will help in the development of important guidelines for future regulations by Brazilian agencies on the use of these substances in fish farming. This paper presents a depletion study for enrofloxacin (ENR) and its main metabolite, ciprofloxacin (CIP), in pacu (Piaractus mesopotamicus) fillets. The depletion study was carried out under monitored environmental conditions, with the temperature controlled at 27 °C to mimic the fish farming conditions in Brazil. ENR was administered orally via medicated feed for 10 consecutive days at daily dosages of 10 mg/kg body weight (b.w.). The fish were slaughtered at 6, 12, and 24 h and 2, 3, 5, 8, 12, 17, and 24 days after the medication period. Considering a maximum residue limit of 100 μg/kg for the sum of the ENR and CIP residues in the fillet, the results obtained in the depletion study allowed the estimation of a half-life for ENR of 2.75 days and a withdrawal period of 23 days. The results obtained in this study are important for the farming of pacu in tropical regions.
One of the most important problems in fish husbandry is effective control of infectious diseases. In that respect one of several strategies is the use of antibacterial agents. Due to their low minimum inhibitory concentration (MIC) value for most susceptible fish pathogens and effective systemic distribution, quinolones is an important group of antibacterial agents used to treat bacterial diseases in fish.It is important that therapeutic regimes are designed to maximise efficacy and thereby minimise the risk of the development of resistant pathogens. In that respect, the study of the pharmacokinetic properties of drugs, in combination with susceptibility test, is an important tool for the establishment of optimal dosage regimes and thus the promotion of their correct use. This review summarises the state of knowledge of the pharmacokinetic properties of the most employed quinolones in fish. Fresh- and seawater, and cold- and warm water species are included in the review.
The plasma kinetics and tissue distribution of enrofloxacin (EF) were investigated in the seabass (Dicentrarchus labrax) after administration by oral gavage and by bath. Plasma and tissue concentrations of EF and of its metabolite ciprofloxacin (CF) were determined by HPLC. After oral treatment (5 mg/kg bw), EF was slowly absorbed and eliminated (Cmax=1.39±0.67 μg/ml at 8 h; T1/2=25 h). EF was distributed efficiently to the extravascular compartment, with concentrations in liver constantly higher than in muscle and skin. Bath treatment (5, 10 or 50 ppm for 4, 8 or 24 h) resulted in plasma and tissue levels that significantly correlated with water drug concentration or time of exposure to medicated water. CF was detected constantly in liver, occasionally in plasma, but never in muscle and skin, suggesting a low degree of metabolic conversion of EF in the seabass. After oral treatment at 5 mg/kg and bath treatment at 50 ppm for 4 h or at 5 ppm for 24 h, ratios between EF peak concentrations in plasma and tissues and MICs of EF against the most common fish pathogens exceeded those indicated as optimal to ensure the bactericidal efficacy of the drug. These dosages of EF are proposed for performing therapeutic trials in the seabass.
The residues of enrofloxacin and its metabolite in Nile tilapia (Oreochromis niloticus) were studied after oral dose of 50 mg/kg for 7 days. To find the differences between Nile tilapia and Chinese shrimp (Penaeus chinensis), the residues of enrofloxacin in P. chinensis were also studied under the same conditions. The results showed that enrofloxacin metabolized into ciprofloxacin in both Nile tilapia and P. chinensis, the maximal concentration of enrofloxacin in muscle, liver and plasma of Nile tilapia were 3.61 μg/g, 5.96 μg/g, 1.25 μg/ml respectively, and ciprofloxacin in muscle was 0.22 μg/g. The maximal concentration of enrofloxacin and ciprofloxacin in P. chinensis were 1.68 μg/g and 0.07 μg/g respectively. The predicted withdrawal time for Nile tilapia was 22 days, and P. chinensis was 12 days under our experiment conditions.The residues of furazolidone [3-(5-nitrofurfurylidenamino)-2-oxazolidinone] and its main metabolite 3-amina-2-oxazolidinone (AOZ) in Nile tilapia were first determined by HPLC/MS. Results showed that after oral dose of 30 mg/kg for 7 days, the maximum concentration of furazolidone in Nile tilapia was 413 μg/kg after 6 h, whereas AOZ residue reached its maximum (31 μg/kg) right after stopping treatment. In contrast to the high metabolic rate of furazolidone, AOZ was very difficult to eliminate in vivo, thus the withdrawal time of furazolidone in Nile tilapia was 22 days at least.
Serum concentrations of enrofloxacin (EF) after intravenous (i.v.) or oral administration of single doses (2.5 and 10 mg/kg b.w., respectively) were investigated in seabream (Sparus aurata L.) kept in seawater at 25–27 °C. The tissue disposition of the drug was studied after oral administration.At prefixed time points, from 1 h to 5 days after administration, blood and edible tissues (muscle plus adherent skin) from 10 individuals in each group were collected and stored at −20 °C.Each serum and tissue sample was essayed for EF by HPLC after liquid–liquid extraction.Serum was also checked for the presence of the metabolite ciprofloxacin (CF).The quantification limits for EF were 0.010 μg/ml in serum and 0.015 μg/g in tissues.Following intravenous administration, considerably high serum concentrations of EF (range 2.605–3.810 μg/ml) were detected during the first 4 h. The concentrations decreased subsequently, indicating a first rapid distribution, followed by a slow phase of elimination. At the last time point of the experiment (120 h), there were still detectable amounts of EF in serum samples (range 0.040–0.087 μg/ml).Enrofloxacin levels of 0.335–1.138 μg/ml were reached in serum within 1 h after in feed administration. The maximum values were measured at 8 h (1.709–2.846 μg/ml), then slowly declined and were measurable (0.048–0.149 μg/ml) for up to 120 h.Compared to serum, lower concentrations of EF were determined in muscle plus skin: 0.156–0.398 μg/g after 1 h, 0.102–2.002 μg/g at 8 h and 0.015–0.031 μg/g at the last sample point.No CF was found in serum.
In this study, the pharmacokinetic profile of enrofloxacin (EF) and its major metabolite, ciprofloxacin (CF), were investigated in brown trout (Salmo trutta fario) (n = 150) after intravenous (i.v.) and oral (p.o.) administrations of a single dose of 10 mg kg− 1 body weight (b.w.) at 10 °C. The plasma concentrations of the drugs were determined by high-performance liquid chromatography (HPLC-UV) from 0.08 to 120 h. Pharmacokinetic parameters were described by the two-compartment open model for intravenous and oral administrations, respectively. After intravenous administration, the elimination half-life (t1/2β), apparent volume of distribution at steady-state (Vss) and total body clearance (Cltot) of enrofloxacin were 19.14 ± 1.51 h, 3.40 ± 0.18 L kg− 1 and 0.14 ± 0.01 L kg h− 1, respectively. After oral administration, the maximum plasma concentration (Cmax), time of maximum concentration (tmax) and bioavailability (F%) were 2.30 ± 0.08 µg mL− 1, 8 h and 78 ± 4%, respectively. Ciprofloxacin was not detected in the present study. The elimination half-life for enrofloxacin following oral administration was longer than values calculated for other animals. After oral administration, the mean plasma concentration was well above the minimum inhibitory concentrations (MICs)—that is, > 0.5 µg mL− 1 at 36 h—for most gram-negative fish pathogens. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in brown trout (S. trutta fario) using oral administration of 10 mg kg− 1 body weight; therefore, it may be effective in the therapy for brown trout diseases.
Fang, X., Liu, X., Liu, W., Lu, C. Pharmacokinetics of enrofloxacin in allogynogenetic silver crucian carp, Carassius auratus gibelio. J. vet. Pharmacol. Therap. 35, 397–401.
The pharmacokinetics of enrofloxacin (EF) was investigated after single intravenous (i.v.) and oral (p.o.) administration of 10 mg/kg body weight (b.w.) in 300 healthy allogynogenetic silver crucian carp at 24–26 °C. The plasma concentrations of EF and its metabolite ciprofloxacin (CF) were determined by high-performance liquid chromatography. After i.v. administration, the plasma concentration–time data were described by an open two-compartment model. The elimination half-life (T1/2β), area under the concentration–time curve (AUC) and total body clearance of EF were 63.5 h, 239.6 μg·h/mL and 0.04 L/h/kg, respectively. Following p.o. administration, the plasma concentration–time data showed a double peak–shaped curve, indicating the possibility of enterohepatic recirculation of EF in allogynogenetic silver crucian carp. The maximum plasma concentration (Cmax), T1/2β and AUC of EF were 4.5 μg/mL, 62.7 h and 205.9 μg·h/mL, respectively. Absorption of EF was very good with a bioavailability (F) of 86%, which could be correlated with the unique structure of the alimentary canal in allogynogenetic silver crucian. CF, an active metabolite of EF, was not detected in this study.
Currently, although enrofloxacin (EF) as a widely used veterinary medicine has begun to apply to treating fish bacterial infections, the researches on the effects of EF on their main drug metabolic enzymes are limited. To investigate the effects of EF on fish cytochromes P450 (CYPs) 1A and 3A, the enzymatic activities and expressions (mRNA and protein) of crucian carp CYP1A and CYP3A after EF administration were examined. For CYP1A, in the in vivo experiments, EF exhibited potent inhibition on the CYP1A-related ethoxyresorufin-O-deethylase (EROD) activity, as well as CYP1A expressions at both protein and mRNA levels, at 24 h after administration with different EF dosages (3, 10, 30, and 60 mg/kg); Furthermore, CYP1A enzymatic activity and expressions at both protein and mRNA levels decreased more with increasing EF dosages. Additionally, the in vitro experimental results showed that, after incubated with microsomes, EF did not change the EROD activity through interacting directly with CYP1A. For CYP3A, the in vitro and in vivo experimental results demonstrated that EF could inhibit the CYP3A-related erythromycin N-demethylase activity in a time-and dose-dependent manner, while it did not suppress CYP3A expressions at both protein and mRNA levels after administration with EF for a short period (no more than 24 h); however, after injection with EF at a high dose (10 mg/kg) for a long period, the CYP3A protein and mRNA reached their lowest levels at 96 and 48 h, respectively. These results indicate that EF can suppress CYP1A expressions in a dose-dependent manner, thereby inhibiting further its catalytic activity; meanwhile, both the interactions of EF with CYP3A and the expressions decrease (protein and mRNA) caused by EF contribute to the CYP3A inhibition.
We investigated the effects of hepatic and renal impairment on the pharmacokinetics of enrofloxacin in Sprague-Dawley rats. Experimental hepatic and renal failure were induced by carbon tetrachloride (CCL(4)) and 5/6 nephrectomy, respectively. After intravenous dosing of enrofloxacin (10 mg/kg), plasma concentrations of enrofloxacin were measured using liquid chromatograph/mass spectrometry. There was no significant effect of hepatic impairment on enrofloxacin pharmacokinetics. However, renal impairment markedly prolonged elimination half life (t(1/2lambdaz)) of enrofloxacin (P < 0.05), comparing with respective control. Total body clearance (Cl(b)) and volume of distribution at steady state (V(ss)) were significantly decreased (P < 0.05) by renal impairment. In conclusion, these results suggested that renal impairment could affect the pharmacokinetics of enrofloxacin.
The fluoroquinolones are a series of synthetic antibacterial agents that are undergoing extensive investigation for both human and veterinary use in the treatment of a variety of bacterial infections. These agents work through the inhibition of DNA gyrase, interfering with the supercoiling of bacterial chromosomal material. As a result, these agents are rapidly bactericidal primarily against gram-negative bacteria, mycoplasma, and some gram-positive bacteria, with most having little to no activity against group D streptococci and obligate anaerobic bacteria. Resistance develops slowly and is almost always chromosomal and not plasmid-mediated. However, development of resistance to the fluoroquinolones and transfer of that resistance among animal and human pathogens have become a hotly debated issue among microbiologists. The fluoroquinolones are a current antimicrobial class whose use in veterinary medicine is being scrutinized. From a pharmacokinetic perspective, these agents are variably but well absorbed from the gastrointestinal tract and almost completely absorbed from parenteral injection sites, and they are well distributed to various tissues in the body. The fluoroquinolones are metabolized and renally excreted, with many of them having approximately equal excretion by the hepatic and the renal excretory systems. The primary toxicity observed at therapeutic doses involves the gastrointestinal system and phototoxicity, although at higher doses central nervous system toxicity and ocular cataracts are observed. Administration to immature animals may result in erosive arthropathies at weight-bearing joints, and administration of high doses to pregnant animals results in maternotoxicity and occasionally embryonic death. The fluoroquinolones are approved for indications such as urinary tract infections and soft tissue infections in dogs and cats and colibacillosis in poultry. Approval for bovine respiratory disease in the United States is being sought. Other indications for which the fluoroquinolones have been used in animal health include deep-seated infections, prostatitis, and other bacterial infections resistant to standard antimicrobial therapy.