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。     

Pharmacokinetics and tissue distribution of oxytetracycline in carp, Cyprinus carpio L., following different routes of administration

Abstract. The objective of this pharmacokinetic study was to investigate absorption, distribution, elimination and bioavailability of oxytetracycline (OTC) in carp, Cyprinus carpio L ., after different routes of administration, OTC was administered intravenously (i.v.), intramuscularly (i.m.) and orally at 60 mg/kg body weight. OTC levels were determined in plasma and several tissues. Analysis of the plasma drug concentration-time curves following i.v. OTC injection revealed three distinct phases. A three-compartment open model was used to derive pharmacokinetic parameters. Compared to mammals, a very extended final elimination half-life was observed (139.8±38.1 h). Following i.m. OTC administration, C_max was 56.8±10.9μg OTC/ml at 14 h post-injection. The Vd area was 2.1 ± 0.66 1/kg. Extreme differences were observed with respect to bioavailability following i.m. and oral administration; approximately 80 and 0.6%, respectively. Following i.m. injection tissue OTC determinations revealed that the drug was accumulating in pronephros, bone tissue and scales. After 21 days the OTC concentrations were 2.9±0.8, 5.2±0.3 and 4.7±3.1 μg/ ml, respectively. In tissue samples from the dorsal region (muscle), including the injection site, OTC could not be demonstrated at that time. The pharmacokinetic data are discussed in relation to the susceptibility of the immune system of fish for modulation.     

Pharmacokinetics of oxolinic acid in black tiger shrimp, Penaeus monodon Fabricius, and the effect of cooking on residues

This study examined the pharmacokinetics and bioavailability of oxolinic acid (OA) in black tiger shrimp Penaeus monodon Fabricius, in brackish water (salinity 10 g L^?1) at 28–29°C, after intra‐sinus (10 mg kg^?1) and oral (50 mg kg^?1) administration and also investigated the net changes of OA residues in the shrimp after cooking (boiling, baking and frying). The haemolymph concentrations of OA after intra‐sinus dosing were best described by a two‐compartment open model. The distribution and elimination half‐lives were 0.84 and 17.7 h respectively. The apparent volume of distribution at a steady state and the total body clearance were estimated to be 2061 mL kg^?1 and 90.1 mL kg^?1 h^?1 respectively. The bioavailability of OA after an oral administration was 7.9%. The peak haemolymph concentration, the time to peak haemolymph concentration and the elimination half‐life after oral administration were 4.20 μg mL^?1, 4 h and 19.8 h respectively. Oxolinic acid muscle and shell levels increased to a maximum (muscle 1.76 μg g^?1 and shell 8.17 μg g^?1) at 4 h post administration and then decreased with the elimination half‐life value of 20.2 and 21.9 h respectively. Residual OA in muscle and shell was reduced by 20–30% by each cooking procedure examined.     

The kinetic profile of oxolinic acid in sharpsnout sea bream, Diplodus puntazzo (Cetti 1777)

The pharmacokinetics of oxolinic acid (OA) were investigated after a single intra‐vascular injection (20 mg kg^?1 fish) in sharpsnout sea bream (90 g), a promising new euryhaline species for Mediterranean fish farming. The distribution half‐life (t_1/2α) and the elimination half‐life (t_1/2β) of OA were calculated to be 0.4 and 10 h respectively. The apparent volume of distribution at steady‐state (V_d(ss)) and total clearance rate (CL_T) of the drug were found to be 2.1 L kg and 0.2 L kg^?1 h^?1 respectively. The bioavailability (F%) of OA following oral administration (40 mg kg^?1 fish) was estimated to be 15%. The results indicate a rapid distribution and elimination of the drug, moderate tissue penetration, but low absorption in sharpsnout sea bream. The kinetic profile of OA found in this species is comparable with that observed in another well‐known sparid, gilthead sea bream.     

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.     

氟苯尼考在猪体内混饲给药药动学研究

选取保育舍25日龄仔猪6头,一次性混饲给药66mg/kg氟苯尼考后,进行药物代谢动力学研究,所得数据经PKS药动学分析软件进行处理。结果表明:混饲给药氟苯尼考后,血药浓度与时间关系均符合二室开放模型,其主要药代动力学参数如下:T1/2β为(25.54±6.66)h,CL/F为(3.87×10-3±9.98×10-5)L/(kg.h),Vd/f为(1.4206±0.3349)L/kg,AUC为(230.878±5.955)mg/(h.L),LagTime为(0.1777±0.2514)h,Tmax为(1.3828±0.6463)h,Cmax为(7.4419±0.1207)μg/mL。从以上参数可以看出,保育舍仔猪一次性混饲给药后,氟苯尼考仍表现出吸收迅速、广泛和消除较慢的特点,与直接口灌给药方式比较,混饲给药的最高血药浓度较低,但消除半衰期明显延长,二者的生物利用度相当。     

Pharmacokinetic disposition of enrofloxacin in brown trout (Salmo trutta fario) after oral and intravenous administrations

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 (t_1/2β), apparent volume of distribution at steady-state (V_ss) and total body clearance (Cl_tot) 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 (C_max), time of maximum concentration (t_max) 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.     

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。     

盐酸沙拉沙星在凡纳滨对虾体内药动学与生物利用度

采用RP-HPLC法研究了在盐度33、水温（28.0±1.0）℃的自然海水中盐酸沙拉沙星单剂量围心腔注射（剂量10 mg·kg-1）和单次药饵投喂（剂量30 mg·kg-1）给药后在凡纳滨对虾（Litopenaeus vannamei）体内的药动学与生物利用度。围心腔注射给药后,血淋巴中药时曲线较适合用二室模型来拟合,而药饵投喂给药后血淋巴中药时曲线较适合采用一级吸收二室模型来拟合。药饵给药下盐酸沙拉沙星在凡纳滨对虾体内的生物利用度（F）为61.6%。药饵投喂给药下大量药物分布到了肝胰腺,肝胰腺血药峰浓度（Cmax）和AUC0-t分别是血淋巴的24.4倍和18.7倍,分别是肌肉的51.9倍和62.0倍;药物在肝胰腺和肌肉中消除都很快,分别在给药后5 d 和36 h低于0.1 mg·kg-1。由此可见,盐酸沙拉沙星药饵给药下吸收好,达峰值高和生物利用度好,且在肌肉和肝胰腺组织中消除快,是较为理想的防治对虾细菌性疾病的抗菌药物。     

A comparative tissue distribution study of oxytetracycline in rainbow trout, Oncorhynchus mykiss (Walbaum), and chinook salmon, Oncorhynchus tshawytscha (Walbaum)

Oxytetracycline (OTC), a broad-spectrum antibiotic, is used widely to treat bacterial diseases in farmed fish. In the present study, the time course of OTC concentrations in freshwater rainbow trout, Oncorhynchus mykiss (Walbaum), and seawater chinook salmon, Oncorhynchus tshawytscha (Walbaum), were compared, tissue by tissue, after receiving a bolus dose of the antibiotic (5 mg kg^–1 or 50 mg kg^–1) intra-arterially (i.a.). The OTC concentration–time profiles of rainbow trout tissues were found to be very similar to those of the corresponding tissues in chinook salmon. Therefore, neither water salinity nor fish species seemed to play an important role in the disposition and elimination of OTC in these salmonids. In a separate experiment, rainbow trout were implanted surgically with a urinary cannula and received a single dose of OTC (50 mg kg^–1) i.a. Urine was collected from the cannula daily for 13 days. The amount of OTC excreted into the bile was found to be larger than that eliminated by the urine. These results show the similarity of OTC pharmacokinetics in freshwater rainbow trout and seawater chinook salmon and render support in using a single fish species to study the pharmacokinetics of a drug for other species in the same taxon.     

Pharmacokinetics and bioavailabilities of 14C-keto-carotenoids, astaxanthin and canthaxanthin, in rainbow trout, Oncorhynchus mykiss

The pharmacokinetics and bioavailabilities of ¹⁴C‐astaxanthin and ¹⁴C‐canthaxanthin were studied in the blood of rainbow trout following intra‐arterial (i.a.) and oral (p.o.) administration. Sixteen months old 1 kg trout were cannulated in the dorsal aorta. [6,7,6′,7′‐¹⁴C]‐keto‐carotenoids were administered i.a. and p.o. at a dose of 573.5 kBq kg^?1 fish body weight for astaxanthin and 836.2 kBq kg^?1 fish body weight for canthaxanthin. After i.a. distribution, total body clearance (Cl_tot) was 17.30±20.29 mL kg^?1 of fish h^?1 for ¹⁴C‐canthaxanthin and 3.30±1.50 mL kg^?1 of fish h^?1 for ¹⁴C‐astaxanthin. The volume of distribution at steady‐state (V_ss) was 208.32±124.79 mL kg^?1 of fish and 71.84±64.15 mL kg^?1 of fish for ¹⁴C‐canthaxanthin and ¹⁴C‐astaxanthin respectively. Less than 0.4% of the administered radioactivity was recovered in urine. Radioactivity (expressed as percent of the dose) excreted in the bile of fish that received ¹⁴C‐canthaxanthin by i.a. route was 20‐fold higher than that observed for fish treated p.o. This ratio was lower for ¹⁴C‐astaxanthin (7.6‐fold). The mean keto‐carotenoid bioavailabilities calculated were 10–15% for both compounds. Findings suggest one daily astaxanthin application is preferable, while 12‐h time intervals between applications are preferable for canthaxanthin.     

A single-dose pharmacokinetic study of oxolinic acid and vetoquinol, an oxolinic acid ester, in Atlantic halibut, Hippoglossus hippoglossus L., held in sea water at 9 °C

The pharmacokinetic properties of the antibacterial agent oxolinic acid were studied after intravenous, intraperitoneal and oral administration to 1.5–3.0 kg Atlantic halibut, Hippoglossus hippoglossus L., held in sea water at 9 °C. Following intravenous injection, the plasma drug concentration-time profile showed two distinct phases. The terminal elimination half-life was estimated to be 52 h, whereas total body clearance (Cl_T) was determined to be 0.044 L kg^–1 h^–1. The volume of distribution at steady state, V_d(ss), was calculated to be 3.0 L kg^–1, indicating good tissue penetration of oxolinic acid in Atlantic halibut. The peak plasma concentration (C_max) and the time to peak plasma concentration (T_max) were estimated to be 1.2 and 2.7 μg mL^–1, and 21.5 and 80 h, respectively, following oral administration of medicated feed or intraperitoneal injection. The corresponding bioavailabilities were calculated to be 15% and 92%, respectively. Oral administration of vetoquinol, the carbitol ester of oxolinic acid, increased the bioavailability of oxolinic acid to 64% and the total bioavailability (oxolinic acid + vetoquinol) to 82%, whereas C_max and T_max values of 6.7 μg mL^–1 and 14.5 h, respectively, for oxolinic acid, and 1.0 μg mL^–1 and 6.3 h, respectively, for vetoquinol were obtained. Based on a minimum inhibitory concentration (MIC) of 0.0625 μg mL^–1 for susceptible strains, a single intraperitoneal injection of 25 mg kg^–1 of oxolinic acid maintains plasma levels in excess of 0.25 μg mL^–1, corresponding to four times the MIC value, for ≈12 days. The corresponding values for a single oral dose of 25 mg kg^–1 of oxolinic acid and vetoquinol were 5 and 10 days, respectively. For resistant strains with a MIC of 1 μg mL^–1, a single oral dose of vetoquinol (25 mg kg^–1) maintained plasma levels in excess of 4 μg mL^–1 for 34 h.     

Kinetic analysis of oxytetracycline residues in Chinese mitten crab,Eriocheir sinensis,muscle following intramuscular administration

Crab culture is a very important economic industry in China. An epidemic of tremor disease of Chinese mitten crabs, Eriocheir sinensis, has become a serious problem in recent years. A spiroplasm has been proved to be the causative agent of this disease. Oxytetracycline (OTC) is used widely in aquaculture and was confirmed to be very effective against this pathogen. In this study, the distribution and depletion patterns of OTC in crab muscle were evaluated following single intramuscular doses of 2, 8 and 40 mg kg^?1 body weight. OTC was detected with a validated HPLC method. Concentration–time profiles were well described by a three‐compartment model with first‐order absorption after a single dose of 8 and 40 mg kg^?1. For comparison, a non‐compartment model was employed. A withdrawal time of 48.29 and 55.92 days was suggested prior to consumption after receiving 8 and 40 mg kg^?1. A recommended therapeutic dose of OTC in theory was calculated to be 36.37 mg kg^?1. OTC was distributed well throughout the body. The elimination of OTC in muscle was slower compared with fish and other crustaceans. A dose of 40 mg kg^?1 is suggested for practical use.     

Pharmacokinetics of oxolinic acid and oxytetracycline in kuruma shrimp, Penaeus japonicus

The pharmacokinetics of oxolinic acid and oxytetracycline were examined in kuruma shrimp (Penaeus japonicus) after intra-sinus (10 and 25 mg/kg, respectively) and oral (50 mg/kg) administration. The shrimp were kept in tanks with recirculated artificial seawater at a salinity of 22–23 ppt. The water temperature was maintained at 25±0.6 °C. The hemolymph concentrations of both drugs after intra-sinus dosing were best described by a two-compartment open model. The distribution and elimination half-lives (t_1/2 and t_1/2β) were found to be 0.59 and 33.2 h for oxolinic acid and 0.45 and 24.7 h for oxytetracycline, respectively. The apparent volume of distribution at a steady state (V_ss) and total body clearance (CL_b) were estimated to be 1309 ml/kg and 28.8 ml/kg/h for oxolinic acid and 748 ml/kg and 22.7 ml/kg/h, respectively. The hemolymph concentration–time curves after oral administration did not fit by the nonlinear least squares method using one- and two-compartment model with first-order absorption in either of the drugs. The peak hemolymph concentration (C_max), the time to peak hemolymph concentration (t_max) and the elimination half-life were found to be 17.8 μg/ml, 7 h and 34.3 h for oxolinic acid and 24.3 μg/ml, 10 h and 33.6 h for oxytetracycline, respectively. The bioavailability (F) after oral administration was 32.9% for oxolinic acid and 43.2% for oxytetracycline. The hemolymph protein binding in vivo was determined to be 36.7±8.5% for oxolinic acid and 22.9±4.8% for oxytetracycline.     

盐酸诺氟沙星在奥尼罗非鱼体内的生物利用度研究

采用高效液相色谱法分别测定静脉注射和混饲口灌奥尼罗非鱼(Oreochromis aureus×O.niloticus)盐酸诺氟沙星后鱼体血液中该药含量变化,用3P97药动学软件分析药动学参数,计算生物利用度.结果表明,在(25±1)℃水温下,以10 mg/kg剂量对奥尼罗非鱼静脉注射和混饲口灌盐酸诺氟沙星,静脉注射药时...     

Bioavailability of oxytetracycline from medicated feed administered to Atlantic salmon (Salmo salar L.) in seawater

Bioavailability of oxytetracycline HCl was investigated in Atlantic salmon (Salmo salar L.) in seawater at 7–8 °C. A group of 80 fish received an intravascular injection of 20 mg kg⁻¹ body weight. Another group of about 90 fish were force-fed with medicated feed containing a dose of 50 mg kg⁻¹ body weight. The oral bioavailability was found to be only 2%.     

Multiple dose pharmacokinetic study of oxolinic acid in cod, Gadus morhua L.

The plasma, muscle and liver distribution and elimination of the antibacterial agent oxolinic acid were studied after multiple oral (p.o.) administration of 10 or 20 mg kg⁻¹ day⁻¹ to cod (Gadus morhua) for 6 days. The fish, held in seawater at 6 and 12°C and weighing 150–250 g were sampled 24 h following last medication. The concentrations in plasma and tissues were clearly dosage and temperature dependent. The distribution from plasma to muscle (muscle/plasma ratio) was higher than that from a single dose study and independent of temperature and dosage. The distribution from plasma to liver (liver/plasma ratio) was lower than the muscle/plasma ratio and according to this study dependent of the administered dosage but independent of temperature. The elimination of oxolinic acid from plasma, muscle and liver was considerably faster following multiple administration compared to a single administration.     

Temperature-dependent pharmacokinetics and tissue distribution of oxolinic acid in sea bass, Dicentrarchus labrax L., after a single intravascular injection

The pharmacokinetics and tissue distribution of oxolinic acid following an intravascular administration (15 mg kg^?1 fish) were determined in sea bass, Dicentrarchus labrax L. (110 g), at 13 °C and 22 °C water temperature. The kinetic profile of the drug was found to be temperature dependent, with increased temperature having a greater effect on distribution after equilibrium and the elimination phase than on the distribution process. The distibution half‐life of oxolinic acid was 1.15 and 2.76 h at 22 °C and 13 °C respectively, whereas the elimination half‐life of the drug was 55 h at 22 °C and 315 h at 13 °C. The values of the apparent volume of distribution (1.44 L kg^?1 at 22 °C and 3.31 L kg^?1 at 13 °C) and the volume of distribution at steady state (5.2 and 14.7 L kg^?1 at the high and low temperature respectively) were considerably different between the two tested temperatures. The total body clearance of the antibiotic was found to be low (1.47 L kg^?1 day^?1 at 22 °C and 0.80 L kg^?1 day^?1 at 13 °C). Lower rates of elimination were found for the liver compared with muscle, the difference increasing with increasing temperature, while elimination rates from the serum were higher than those of other tissues, especially at the high temperature.