The influence of antibiotics on the immune system: immuno-pharmokinetic investigations on the primary anti-SRBC response in carp, Cyprinus carpio L., after oxytetracycline injection

Abstract. The present study was performed to obtain further details on the immuno-modulating effects of oxytetracycline (OTC) in carp, Cyprinus carpio L. The immuno-logical study was extended by investigating the pharmacokinetic behaviour of OTC. Oxytetracycline, at a dosage of 60 mg/kg, was administered five times intra-peritoneally at 3-day intervals; the first injection was given 1 day before immunization. The kinetics of the primary anti-sheep red blood cell (SRBC) response, during a short-term OTC treatment revealed that the kinetics of the plaque-forming cell (PFC) response was not significantly affected by OTC nor its solvent. In contrast, the number of plaque-forming cells was significantly decreased. The anti-SRBC antibody production was delayed by 2–4 days in both experimental groups (OTC and solvent). However, within 12–14 days post-immunization, the same antibody levels were detected as in the control group. High OTC plasma levels (>50 μg/ml) were detected about 10 h after a single i. p. injection. A mean plasma elimination half-life (T¹/₂) of 34·5 h was calculated.     

Pharmacokinetics and bioavailability of oxytetracycline in vannamei shrimp (Penaeus vannamei) and the effect of processing on the residues in muscle and shell

The present study examined the pharmacokinetics and bioavailability of oxytetracycline (OTC) in vannamei shrimp (Penaeus vannamei) after intra-sinus (10 mg/kg) and oral (10 and 50 mg/kg) administration and also investigated the net changes of OTC residues in the shrimp after the thermal, acid and alkaline processing methods. The hemolymph concentrations of OTC after intra-sinus dosing were best described by a two-compartment open model. The oral bioavailability was found to be 48.2 and 43.6% at doses of 10 and 50 mg OTC/kg, respectively. The peak hemolymph concentrations after 10 and 50 mg OTC/kg doses were 3.37 and 17.4 μg/ml; the times to peak hemolymph concentrations were 7 and 10 h. The elimination half-lives were found to be 15.0 and 11.5 h for the low and high dose, respectively. The residual OTC was rapidly eliminated from muscle with the elimination half-life value of 19.4 and 15.4 h, respectively, for the groups treated with doses of 10 and 50 mg/kg. The residual OTC levels in the muscle fell below the MRL (0.2 μg/g) at 72 and 96-h post-dosing at dose levels of 10 or 50 mg/kg, respectively. Residual OTC levels in muscle and shell were approximately 20–50% lower in the thermal treatment such as boiling, baking and frying. By the acid treatment, OTC residues were reduced to >80%, while those were reduced to around 30% by alkaline treatment.     

土霉素在锯缘青蟹体内的药物代谢和消除规律

采用高效液相色谱法检测土霉素,研究土霉素口灌给药途径下在锯缘青蟹体内的药代动力学。锯缘青蟹口灌给药土霉素50 mg/kg后,其血浆、肌肉和肝胰脏中的药峰浓度分别为16.78±1.98 mg/L、9.39±2.12μg/g和32.12±6.12μg/g,达峰时间分别为4 h、8 h和4 h。血浆中土霉素浓度-时间关系曲线符合一级吸收的二室开放动力学模型。土霉素在锯缘青蟹体内分布广泛,其表观分布容积(Vd)为2.129 L/kg;分布半衰期(t1/2α)和消除半衰期(t1/2β)分别为3.200 h和47.856 h,总体清除率(CLs)为0.063 mL/(kg.h)。肌肉和肝胰脏中土霉素浓度与时间关系的药动学参数采用统计矩原理分析,其消除半衰期(t1/2 z)分别为60.145 h和71.009 h,总体清除率(CLz)分别为0.054 g/(kg.h)和0.037 g/(kg.h)。土霉素在精巢和卵巢中达峰时间分别为8 h和12 h,峰浓度分别为9.83μg/g和10.26μg/g。给药后24 d时,血浆、肌肉、肝胰脏、精巢和卵巢中土霉素含量都已低于0.10μg/g。土霉素在锯缘青蟹体内消除比较缓慢。     

A single-dose pharmacokinetic study of oxolinic acid and vetoquinol,an oxolinic acid ester,in cod,Gadus morhua L., held in sea water at 8 degrees C and in vitro antibacterial activity of oxolinic acid against Vibrio anguillarum strains isolated from diseased cod

The pharmacokinetic properties of the antibacterial agent oxolinic acid and vetoquinol, the carbitol ester of oxolinic acid, were studied after intravenous (i.v.) and oral (p.o.) administration to 100-150 g cod, Gadus morhua L., held in sea water at 8 degrees C. Following i.v. injection, the plasma drug concentration-time profile showed two distinct phases. The distribution half-life (t1/2alpha) was estimated at 1.3 h, the elimination half-life (t1/2beta) as 84 h and the total body clearance (Cl(T)) as 0.047 L kg(-1) h(-1). The volume of distribution at steady state, Vd(ss) was calculated to be 5.5 L kg(-1), indicating good tissue penetration of oxolinic acid in cod. Following p.o. administration of oxolinic acid or vetoquinol, the peak plasma concentrations (C(max)) of oxolinic acid and the time to peak plasma concentrations (T(max) were estimated to be 1.2 and 2.5 microg mL(-1) and 24 and 12 h, respectively. The bioavailabilities of oxolinic acid following p.o. administration of oxolinic acid and vetoquinol were calculated to be 55 and 72%, respectively. The in vitro minimum inhibitory concentration (MIC) values of oxolinic acid against three strains of Vibrio anguillarum isolated from diseased cod were 0.016 microg mL(-1) (HI-610), 0.250 microg mL(-1) (HI-618) and 0.250 microg mL(-1) (HI-A21). Based on a MIC value of 0.016 microg mmL(-1) a single p.o. administration of 25 mg kg(-1) of oxolinic acid maintains plasma levels in excess of 0.064 microg mL(-1), corresponding to four times the MIC-value, for approximately 12 days. The analogous value for a single p.o. dose of 25 mg kg(-1) of oxolinic acid administered as vetoquinol was 13 days.     

Pharmacokinetics and tissue distribution of oxytetracycline in sea bass, Dicentrarchus labrax, at two water temperatures

A pharmacokinetic study of oxytetracycline (OTC) following an intravascular administration (40 mg/kg) was carried out in sea bass, Dicentrarchus labrax (110 g), at 13.5 and 22 °C water temperature. Blood, muscle and liver samples were taken at 1, 2, 4, 8, 16, 32, 64 and 128 h post-injection. The plasma data were conformed to a two-compartment model. The kinetic profile of the drug was found to be temperature dependent. The absorption half-life (t_1/2) of OTC was 0.98 and 0.192 h at 13.5 and 22 °C, respectively, whereas the elimination half-time (t_1/2β) of the drug was 69 h at 13.5 °C and 9.65 h at 22 °C. The apparent volume of distribution of the drug at steady state [V_d(ss)] was 5.62 l/kg at 13.5 °C and 2.59 l/kg at 22 °C. The mean residence time (MRT) of OTC was found to be 37.7 h at 22 °C and 71 h at 13.5 °C. The total clearance of the drug (CL_T) was calculated to be 73.5 and 68.7 ml/kg/h at 13.5 and 22 °C, respectively.

Liver levels indicated higher OTC values than respective muscle levels at all time points and for both temperatures. The elimination of OTC from tissues tested was faster at the high temperature, whereas the drug was eliminated faster from liver compared to muscle when comparisons are made at the same temperature.     

盐酸土霉素在奥尼罗非鱼体内的药代动力学及残留研究

在水温(25±2)℃条件下,以15 mg/kg鱼体重的剂量给奥尼罗非鱼单次口灌盐酸土霉素,采用高效液相色谱法测定血浆和肌肉组织中的药物浓度,研究盐酸土霉素在奥尼罗非鱼体内的代谢及消除规律。结果显示:血药时间数据符合一级吸收二室开放模型,半衰期(T1/2Ka、T1/2α、T1/2β)分别为4.79、4.10、45.20 h,最大血药浓度为1.50μg/m L,达峰时间为7.30 h,药时曲线下面积(AUC)为42.35μg·h/m L。肌肉作为可食性组织,选取肌肉组织作为残留检测的靶组织,以0.1 mg/kg为最高残留限量,在本试验条件下,建议休药期不低于10 d。     

A single‐dose pharmacokinetic study of emamectin benzoate in cod,Gadus morhua L., held in sea water at 9 °C

The pharmacokinetic profile of the antiparasitic agent emamectin benzoate was studied in plasma after intravenous (i.v.) injection and in plasma, muscle and skin following oral (p.o.) administration to cod, Gadus morhua, held in sea water at 9 °C and weighing 100–200 g. Following i.v. injection, the plasma drug concentration‐time profile showed two distinct phases. The plasma distribution half‐life (t_1/2α) was estimated as 2.5 h, the elimination half‐life (t_1/2β) as 216 h, the total body clearance (Cl_T) as 0.0059 L kg^?1 h^?1 and mean residence time (MRT) as 385 h. The volume of distribution at steady state, V_d(ss), was calculated to be 1.839 L kg^?1. Following p.o. administration the peak plasma concentration (C_max) was 15 ng mL^?1, the time to peak plasma concentration (T_max) was 89 h and t_1/2β was 180 h. The highest concentration in muscle (21 ng g^?1) was measured after 7 days and t_1/2β was calculated to be 247 h. For skin, a peak concentration of 28 ng g^?1 at 3 days was observed and a t_1/2β of 235 h was determined. The bioavailability following p.o. administration was calculated to be 38%.     

Oxytetracycline Residue in Hybrid Striped Bass Muscle

Hybrid striped bass ( Morose saxatilis male × M. chrysops female) were injected with 25 and 50 mg oxytetracycline (OTC) per kg of fish. Rate of elimination of OTC from muscle tissue and inhibition of bacteria by muscle injected with OTC were studied. OTC residue in muscle of fish injected with 50 mg OTC/kg fish was much higher (P < 0.01) than that in fish injected with 25 mg/kg and took a longer time to clear from the muscle. In fish injected at 25 mg OTC/kg of fish, OTC was completely eliminated from muscle in 24 d; the rate of elimination constant (β) was 0.278/day and the half-life (t_1/2) 2.5 d. In fish injected at 50 mg OTC/kg of fish, the OTC was not depleted in fish muscle until 32 d after injection; the rate of elimination constant 13 was 0.265/day and the half-life was 2.6 d. No statistical difference was found in muscle OTC residue between male and female fish. Size of fish (16.5 to 21.5 cm and 21.6 to 25.5 cm) made little difference in OTC residue in muscle. Muscle removed from fish injected with 25 mg/kg OTC 12 d after injection inhibited the growth of Vibrio anguillarum, V. ordalii and Aeromonas hydrophila in cultures.     

Therapeutic aminoglycoside antibiotic levels in brown shark, Car char hinus plumb eus (Nardo)

Abstract. The kinetics of gentamicin and tobramycin in juvenile brown sharks, Carcharhinus plumbeus (Nardo), were studied using a commercially available radioimmune assay (Clinical Assays, Cambridge, Massachusetts). Preliminary recovery studies in vitro demonstrated 95% recovery of antibiotic spiking with no detection of interfacing substances. There were no differences between serum and plasma data using this assay. Both drugs demonstrated distinct two-compartment characteristics. The mean half-life of the alpha component was 5.4±1.0 h for gentamicin and 3.2±0.5 h for tobramycin. The half-lives of the beta components were markedly longer, 54±4.9 h for gentamicin and 48±2 h for tobramycin. The experimental designs could not exclude third compartments. A therapeutic dosage schedule for gentamicin of 2 mg/kg intramuscularly followed by 1 mg/kg at 8 and 72 h was tested. This schedule avoided plasma levels greater than 12μg/ml and troughs greater than 2 μg/ml but more frequent administration may be required to treat infections with bacteria which are less sensitive to aminoglycoside antibiotics. A therapeutic tobramycin schedule of 2.5 mg/kg intramuscularly followed by 1.0 mg/kg, 4 h later and daily thereafter, achieved plasma levels within the human therapeutic range (5.8μg/ml) on the second day of therapy. Levels considered toxic to humans were not reached for 5 days.     

土霉素在红鳍东方鲀体内的残留及休药期研究

在14±2℃水温条件下,连续5d对红鳍东方鲍口灌剂量为100mg／kg的土霉素,采用高效液相色谱法测定了停药后血清、肌肉、肝脏组织中的药物含量、消除速率常数和消除半衰期,提出了该温度下的休药期。研究表明,在停药2d后红鳍东方鲍血清和肌肉中的药物浓度达到峰值,分别为1．092μg／ml和0．806μg／g;停药3d后肝脏内土霉素浓度达到峰值1．229μg／g,土霉素在血清、肌肉和肝脏中的消除半衰期分别为23．8、22．4和26．8d;土霉素在红鳍东方纯肌肉组织中降到0．1μg／g残留限量的时间为58d,降到0．05μg／g残留限量的时间为81d。     

Single Intravascular and Oral Dose Pharmacokinetics of Mebendazole in Blunt Snout Bream,Megalobrama amblycephala

Mebendazole (MBZ) is a broad‐spectrum benzimidazole methylcarbamate anthelmintic used widely in animal husbandry and aquaculture. However, there is no information available on the pharmacokinetic behavior of MBZ in blunt snout bream, Megalobrama amblycephala. In this study, pharmacokinetic parameters of MBZ were estimated in blunt snout bream after intravascular (3 mg/kg body weight [BW]) and oral (20 mg/kg BW) administration. The analyses of plasma samples were performed using ultra performance liquid chromatography with ultraviolet detector. After intravascular administration, plasma concentration–time curves were best described by a two‐compartment open model. The distribution half‐life (t_1/2α), elimination half‐life (t_1/2β), and area under the concentration–time curve (AUC) of blunt snout bream were 0.1 h, 27.9 h, and 56666.0 h.µg/L, respectively. After oral administration, a one‐compartment open model with first‐order absorption best fit the plasma data. The absorption half‐life (t_1/2Ka), elimination half‐life (t_1/2Ke), peak concentration (C_max), time‐to‐peak concentration (T_max), and AUC of blunt snout bream were estimated to be 1.9 h, 34.6 h, 918.1 µg/L, 8.4 h, and 54201.4 h.µg/L, respectively. The oral bioavailability (F) was 14.3 %. The pharmacokinetics of MBZ in blunt snout bream displayed low bioavailability, relatively rapid absorption, and relatively rapid elimination.     

肌注和口灌氟苯尼考在吉富罗非鱼体内的药代动力学

通过肌内注射、口灌两种给药方式,研究氟苯尼考在罗非鱼体内的药物代谢动力学特征。把吉富罗非鱼(GIFT Oreochromis niloticus)随机分成2组,控制水温在30℃,以15 mg/kg分别单剂量肌内注射、口灌给药。经高效液相色谱法(HPLC)测定血浆中氟苯尼考浓度,用Win Nonlin药动学软件分析药动学参数。结果表明:肌内注射氟苯尼考后,药物吸收较慢,消除较快,达峰时间(T_(max))=4 h,峰浓度(C_(max))=4.64μg/mL,消除半衰期(T_(1/2λ)z L)=10.45 h,药-时曲线下面积(AUC)=91.06μg·h/mL。口灌氟苯尼考后,药物吸收较快,消除较慢,T_(max)=1 h,C_(max)=5.92μg/mL,T_(1/2λ)z L=13.13 h,AUC=61.96μg·h/mL。肌内注射、口灌氟苯尼考后,二者的药动学参数差异显著,这一差异表明肌内注射给药吸收相对较慢,但更为完全(肌内注射氟苯尼考的AUC明显较大),消除相对较快。     

Pharmacokinetics of sulfamonomethoxine in tongue sole (Cynoglossus semilaevis) after intravenous and oral administration

The pharmacokinetic profiles of sulfamonomethoxine (SMM) were investigated in flatfish tongue soles in the present study. After a single injection of SMM (40 mg/kg BW) to caudal vein of tongue sole at 20 °C, plasma drug concentration versus time data were best fitted to a three-compartment model, characterized with 0.2, 5.7, and 80.4 h for the half-life (t _1/2) of fast distribution, slow distribution, and elimination, respectively. The apparent volume of distribution was 0.1 L/kg, and the body clearance was 0.03 L/h/kg. After oral administration of SMM (200 mg/kg BW) to tongue soles at 20 °C, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t _1/2ka) and elimination (t _1/2β ) were 1.7 and 95.7 h, respectively. The maximal absorption concentration (C _max) was estimated as 58 mg/L at 2.5 h, and the mean systemic bioavailability (F) was 39.5 % in tongue soles after oral administration.     

Pharmacokinetics of oxolinic acid in gilthead sea bream, Sparus aurata L.

This is the first study on the pharmacokinetic parameters of oxolinic acid (OA) in gilthead sea bream, Sparus aurata L. The kinetic profile of OA was studied after a single intravascular injection (20 mg kg⁻¹) in 100 g fish at 20 °C. The distribution half-life ( t _1/2α) and the elimination half-life ( t _1/2β) of the drug were found to be short (0.51 and 12.60 h, respectively). The drug penetration from the plasma to the tissues was adequate as the apparent volume of distribution of the drug at steady-state ( V _d(ss)) was found to be 2.11 L kg⁻¹. The mean residence time ( MRT ) of OA was short (14.25 h) and the total clearance rate ( Cl _T) of the drug was low (0.15 L kg⁻¹ h⁻¹). The bioavailability ( F %) of OA following oral administration (30 mg kg⁻¹) was also low (14%). Maximum values were observed for muscle at 0.5 h after injection, with levels declining as with subsequent sampling. At the first two time points (0.5 and 1 h) plasma levels of OA were higher than muscle, however, the reverse was evident for subsequent samples. Following oral administration, highest muscle levels were found at 16 h and, with the exception of the 24-h sampling, muscle OA concentrations were higher than plasma at all time points. The fast elimination of OA suggests short withdrawal times with reference to human consumption of treated fish.     

Multiple-dose pharmacokinetic and depletion studies of sarafloxacin in Atlantic salmon, Salmo salar L.

Abstract. Two multiple-dose pharmacokinetic and depletion studies with sarafloxacin hydrochloride in feed pellets were conducted with Atlantic salmon at 12.1 ± 1.1 †C and 9.3 ± 1.5†C, respectively. The dose regimens used were 10mg sarafloxacin kg^-1 biomass for 10 days, and 20mg sarafloxacin kg^-1 biomass for 5 days. In the 10-day study, the highest average concentrations of sarafloxacin in plasma, muscle and liver were 0.14, 0.39 and 0.88μgg(ml)^-1, respectively. In the 5-day study, the highest average concentrations in plasma, muscle, liver and skin were 0.40, 0.61, 1.56 and 0.19μg(ml)^-1, respectively. A comparison between the individual plasma concentrations and the corresponding tissue concentrations revealed significantly higher concentrations in tissue than in plasma during the depletion phase. A similar comparison made in the therapeutic phase from 3 days after first medication to one day after the last medication revealed significantly higher concentrations in liver and muscle than in plasma, and significantly lower concentrations in skin than in plasma. On withdrawal of the drug, sarafloxacin concentrations in plasma and the different tissues declined rapidly, Sarafloxacin was not detected in any plasma sample taken 6 days or more after the end of medication. The corresponding figures for muscle, skin and liver tissues were 14, 20 and 22 days, respectively. The half-lives of sarafloxacin varied in the different tissues included in the studies. The half-life was shortest in plasma, and increased in ascending order in muscle, liver and skin.     

Pharmacokinetic study of oxytetracycline in healthy and vibriosis-infected ayu (Plecoglossus altivelis)

The pharmacokinetics and bioavailability of oxytetracycline (OTC) were examined in healthy and vibriosis-infected ayu (Plecoglossus altivelis). Water temperature was maintained at 18.0 ± 0.3 °C in all experiments. Serum concentrations of OTC in healthy fish after intravascular administration (25 mg kg⁻¹ body weight) were best described by a two-compartment model, whereas serum concentration-time curves after oral administration (100 mg kg⁻¹ body weight) in healthy and infected ayu could not be fitted by the nonlinear least squares method using one- and two-compartment models with first-order absorption. The estimated bioavailability after oral administration was 9.3% for healthy fish and 3.8% for infected fish. The elimination half-lives of serum, muscle, liver and kidney were 53.1 h, 106 h, 125 h and 117 h for healthy fish, and 63.2 h, 92.9 h, 107 h and 123 h for infected fish, respectively. A significant difference in bioavailability was revealed between healthy fish and infected fish, whereas elimination was similar in both fish. Serum protein binding in vivo of OTC was 68.0 ± 2.8% for healthy fish and 69.9 ± 4.4% for infected fish.     

土霉素在奥尼罗非鱼体内的药动学研究

在(21±1)℃的水温条件下,以50 mg/kg的单剂量,分别给奥尼罗非鱼(Oreochromis aureus×O.niloticus)水剂口灌和混饲口灌土霉素,用高效液相色谱法(HPLC)检测给药后各个时间点的血药浓度。结果显示:最低检测限为0.005μg/mL,线性范围为0.005~4μg/mL。水剂口灌组和混饲口灌组的药时数据均符合具时滞的二室开放动力学模型,水剂口灌组的动力学方程为:Ct=0.231e-0.028(t-0.010)+0.353e-0.011(t-0.010)-0.584e-0.468(t-0.010),混饲口灌组动力学方程:Ct=0.839e-0.057(t-0.459)+0.442e-0.013(t-0.459)-1.281e-0.282(t-0.459)。水剂口灌组及混饲口灌组主要药动学参数分别为:吸收半衰期(t1/2ka)为1.481 h,2.458 h;分布半衰期(t1/2α)为24.834 h,12.193 h;消除半衰期(t1/2β)为60.312 h,51.533 h;达峰时间(Tmax)为7.230 h,8.221 h;最大血药浓度(Cmax)为0.494μg/mL,0.796μg/mL;血药浓度-时间曲线下面积(AUC)=37.74μg.h/mL,43.075μg.h/mL。这些参数表明,水剂口灌比混饲口灌吸收快,分布和消除慢,在血液中达到峰浓度的时间更短,但峰浓度值比混饲口灌低。     

Hepatopancreatic and muscular distribution of oxytetracycline antibiotics in farmed pacific white shrimp (Penaeus vannamei): a physiological‐based pharmacokinetic model approach

Oxytetracycline (OTC) pharmacokinetic models previously used to investigate Penaeus vannamei have not addressed the specific problems related to drug distribution/disposition in particular tissues. This study aimed to provide an insight into OTC kinetics in the hepatopancreas and muscle based on a physiological model approach. Adult male P. vannamei at the C‐D₀ inter‐moulting stage were randomly assigned to intra‐sinus and oral administrations. In the intra‐sinus group, shrimps were dosed via the ventral sinus at an OTC level of 10.0 μg g^?1 body weight, while in the oral one, they were force fed at a dose level of 50.2 μg g^?1. The medicated animals were sampled at various time intervals until 170 h after dosing. Haemolymph, muscle and hepatopancreas samples were taken and OTC levels were determined using the validated HPLC method. A model focused on the hepatopancreas and muscle was developed. Oxytetracycline pharmacokinetic profiles in particular tissues were fitted into the model with an R² of between 0.6568 and 0.9904. Oxytetracycline muscular distributions were essentially identical for both groups and the drug did not accumulate in muscle. The distributions in the hepatopancreas for both groups were extensive, whereas that for oral administration was approximately 2.3 times greater than that for the intra‐sinus one. It was demonstrated that hepatopancreatic OTC may undergo significant first‐pass elimination with non‐linear kinetics.     

Effect of route of administration and carrier on bioavailability and kinetics of astaxanthin in Atlantic salmon Salmo salar L.

This study examined astaxanthin bioavailability and kinetics in adult Atlantic salmon Salmo salar L., following two different routes of astaxanthin administration (oral vs. intraperitoneal (i.p.) injection) using two different carriers of the pigment (gelatin vs. sesame oil). The dorsal aorta of adult Atlantic salmon (mean initial weight 950 g) was cannulated. The fish received a single dose of astaxanthin (572 μg kg^?1) in sesame oil or (514 μg kg^?1) in gelatin via the oral or i.p. route. Plasma was sampled regularly up to 72 h post oral administration and up to 510 h post i.p. injection. The astaxanthin concentration–time curves from plasma were best fit to a one‐compartment pharmacokinetic model for each of the four treatments. The gelatin carrier resulted in higher availability of astaxanthin compared to the sesame oil carrier. The bioavailability for astaxanthin in sesame oil was only 38.7% of that in gelatin by i.p. injection, and only 53.5% of that in gelatin by oral administration. Higher availability of astaxanthin was observed when i.p. injection was used compared to oral administration. The bioavailability for astaxanthin administered orally was only 12% of that by i.p. injection in sesame oil, and only 8.7% of that by i.p. injection in gelatin.     

Pharmacokinetics and bioavailability of flumequine and oxolinic acid after various routes of administration to Atlantic salmon in seawater

The present preclinical study was performed to investigate the pharmacokinetics of flumequine in Atlantic salmon (Salmo salar L.) in seawater after administration of different doses and dosage formulations. Flumequine was administered intravenously (dose 4.9 mg/kg fish) and orally from the drug delivery system Aqualets as Apoquin 5 g/kg (dose 25 mg/kg) and 10 g/kg (dose 50 mg/kg), respectively. Experiments were carried out with oxolinic acid administered in the same way for the purpose of comparing the two compounds. The seawater temperature was 5±0.2°C in all experiments.

The pharmacokinetic calculations showed that the distribution half-life for flumequine was and for oxolinic acid . The drugs were absorbed rapidly, and flumequine reached a plasma concentration of C_max = 2.26 μg/ml after a single oral dose of 25 mg/kg, whereas oxolinic acid reached C_max = 0.99 μg/ml. The apparent bioavailability of flumequine was found to be 40–45%, whereas the apparent bioavailability of oxolinic acid varied from 25% at a dose of 50 mg to 40% at a dose of 25 mg/kg body weight of fish. The distribution profile of flumequine in the various compartment of fish appeared to be different from that of oxolinic acid. After a single oral dose (25 mg/kg) the areas under the concentration-time curves showed that flumequine was 2.3 times more concentrated in plasma and 2.6 times more concentrated in liver compared to oxolinic acid. In muscle the difference was less pronounced, flumequine being 1.4 times more concentrated than oxolinic acid.