乳酸恩诺沙星可溶性粉在鸡体内的药动学研究

24只苏禽黄羽肉鸡随机分成2组,分别按10 mg/kg体重剂量静注和内服乳酸恩诺沙星。测定乳酸恩诺沙星在鸡体内的药动学参数和生物利用度。恩诺沙星血药浓度数据用3p87计算机软件处理。静注乳酸恩诺沙星后的血药浓度-时间数据符合二室开放模型,主要动力学参数:t1/2α(0.45±0.16)h,t1/2β(7.02±1.42)h,CL(s)(0.38±0.10)L/kg/h,AUC(23.69±5.56)(mg/L)×h。内服乳酸恩诺沙星的血药浓度时间数据,符合有吸收因素二室模型,主要动力学参数:t1/2ka(0.60±0.01)h,t1/2ke(8.25±1.73)h,tpeak(2.44±0.17)h,Cmax(1.44±0.30)mg/L,AUC(20.74±3.80)(mg/L)×h,F 87.54%。结果表明,乳酸恩诺沙星可溶性粉在鸡体内具有吸收快、分布广、消除较慢以及内服生物利用度高的药动学特征。     

Pharmacokinetic evaluation of enrofloxacin administered orally to healthy dogs.

Enrofloxacin was administered orally to 6 healthy dogs at dosages of approximately 2.75, 5.5, and 11 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosage regimens. Serum and tissue cage fluid (TCF) concentrations of enrofloxacin were measured after the first and seventh treatments. The mean peak serum concentration occurred between 1 and 2.5 hours after dosing. Peak serum concentrations increased with increases in dosage. For each dosage regimen, there was an accumulation of enrofloxacin between the first and seventh treatment, as demonstrated by a significant (P = 0.001) increase in peak serum concentrations. The serum elimination half-life increased from 3.39 hours for the 2.75 mg/kg dosage to 4.94 hours for the 11 mg/kg dosage. Enrofloxacin accumulated slowly into TCF, with peak concentrations being approximately 58% of those of serum. The time of peak TCF concentrations occurred between 3.8 hours and 5.9 hours after drug administration, depending on the dosage and whether it was after single or multiple administrations. Compared with serum concentrations (area under the curve TCF/area under the curve serum), the percentage of enrofloxacin penetration into TCF was 85% at a dosage of 2.75 mg/kg, 83% at a dosage of 5.5 mg/kg, and 88% at a dosage of 11 mg/kg. All 3 dosage regimens of enrofloxacin induced continuous serum and TCF concentrations greater than the minimal concentration required to inhibit 90% (MIC90) of the aerobic and facultative anaerobic clinical isolates tested, except Pseudomonas aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic properties of enrofloxacin in rabbits.

The pharmacokinetic properties of the fluoroquinolone antimicrobial enrofloxacin were studied in New Zealand White rabbits. Four rabbits were each given enrofloxacin as a single 5 mg/kg of body weight dosage by IV, SC, and oral routes over 4 weeks. Serum antimicrobial concentrations were determined for 24 hours after dosing. Compartmental modeling of the IV administration indicated that a 2-compartment open model best described the disposition of enrofloxacin in rabbits. Serum enrofloxacin concentrations after SC and oral dosing were best described by a 1- and 2-compartment model, respectively. Overall elimination half-lives for IV, SC, and oral routes of administration were 2.5, 1.71, and 2.41 hours, respectively. The half-life of absorption for oral dosing was 26 times the half-life of absorption after SC dosing (7.73 hours vs 0.3 hour). The observed time to maximal serum concentration was 0.9 hour after SC dosing and 2.3 hours after oral administration. The observed serum concentrations at these times were 2.07 and 0.452 micrograms/ml, respectively. Mean residence times were 1.55 hours for IV injections, 1.46 hours for SC dosing, and 8.46 hours for oral administration. Enrofloxacin was widely distributed in the rabbit as suggested by the volume of distribution value of 2.12 L/kg calculated from the IV study. The volume of distribution at steady-state was estimated at 0.93 L/kg. Compared with IV administration, bioavailability was 77% after SC dosing and 61% for gastrointestinal absorption. Estimates of predicted average steady-state serum concentrations were 0.359, 0.254, and 0.226 micrograms/ml for IV, SC, and oral administration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative pharmacokinetics of enrofloxacin and ciprofloxacin in chickens

The pharmacokinetics of enrofloxacin (EFX) and ciprofloxacin (CFX) was investigated in broiler chickens. Each antimicrobial was administered intravenously at a dose of 5 mg/kg body weight. Blood was taken in different preset times: prior and at 0.03, 0.06, 0.13, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h following drug administration. The concentrations of EFX and CFX in plasma were determined by high pressure liquid chromatography (HPLC). Plasma concentrations vs. time were analysed by a compartmental independent pharmacokinetic model that provided the most important kinetic parameters. Statistically significant differences between the two antimicrobials were found for most of the pharmacokinetic parameters: Area under the curve (AUC), area under first moment curve (AUMC), mean residence time (MRT), total body cleareance (ClB), volume of distribution beta (Vd beta) and volume of distribution at the steady state (Vd(ss)). Both antimicrobials were widely distributed in chickens throughout the body with a mean Vd(ss) of 1.98+/-0.18 L/kg for EFX, and 4.04+/-0.69 L/kg for CFX. The ClB for CFX was five times higher than that obtained for EFX. AUC, MRT and the diminished half time for EFX were two-four times higher than those obtained for CFX. These results indicate that CFX remains in the body for less time than the other quinolone. This characteristic of CFX suggests the advantage of a shorter withdrawal time for food producing animals treated with this antimicrobial.     

Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs

OBJECTIVE: To examine pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs following simultaneously administered SC injections of these drugs. ANIMALS: 10 Beagles (4 males and 6 females). PROCEDURE: All dogs underwent the following 3 drug administration protocols with a 4-week washout period between treatments: flunixin administration alone (1 mg/kg, SC); simultaneous administration of flunixin (1 mg/kg, SC) and enrofloxacin (5 mg/kg, SC); and enrofloxacin administration alone (5 mg/kg, SC). Blood samples were collected from the cephalic vein at 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12, and 24 hours following SC injections, and pharmacokinetic parameters of flunixin and enrofloxacin were calculated from plasma drug concentrations. RESULTS: Significant increases in the area under the curve (32%) and in the elimination half-life (29%) and a significant decrease (23%) in the elimination rate constant from the central compartment of flunixin were found following coadministration with enrofloxacin, compared with administration of flunixin alone. A significant increase (50%) in the elimination half-life and a significant decrease (21%) in the maximum plasma drug concentration of enrofloxacin were found following coadministration with flunixin, compared with administration of enrofloxacin alone. CONCLUSIONS AND CLINICAL RELEVANCE: The observed decrease in drug clearances as a result of coadministration of flunixin and enrofloxacin indicates that these drugs interact during the elimination phase. Consequently, care should be taken during the concomitant use of flunixin and enrofloxacin in dogs to avoid adverse drug reactions.     

中药复方禽病康在鸡体内的药代动力学研究

以血清一氧化氮（NO）变化为药理效应指标,用药理效应法研究了中药复方制剂禽病康在免疫抑制雏鸡体内的药代动力学特征,并探讨了其扶正固本、增强机体免疫功能的作用机制。结果表明,免疫抑制雏鸡单剂量口服禽病康的效应动力学参数为：最低起效剂量Xmin=2.61 g/kg,效应呈现半衰期t1/2ka（E）=0.61 h,效应达峰时间tp（E）=1.82 h,效应消除半衰期t1/2b（E）=3.25 h;以时间-体存量进行数学模型拟合,符合一级吸收二室模型,其数学表达式为C=24.221e-0.931t＋3.485e-0.012t＋27.705e-1.166t。禽病康药代动力学结果表明其口服后吸收较快,分布也快,而消除较慢,体内存留时间长,药效维持时间长。     

盐酸小檗碱在鸡体内的药动学研究

探讨盐酸小檗碱在鸡体内的药动学特征。鸡以3mg／kg和50mg／kg剂量静脉注射和口服给药,采用HPLC法测定血浆中盐酸小檗碱的质量浓度。血药浓度-时间数据经DAS药代动力学分析软件处理,计算出药动学参数。结果表明：盐酸小檗碱静脉注射药时曲线符合三室开放模型,主要药动学参数分别为：t1／2β为（0．41±0．24）h,t1／2γ为（3．66±1．06）h,Vc为（25．49±21．77）L·kg^-1,CL为（43．20±16．21）L·h^-1·kg^-1,AUC为（78．92±30．58）μg·L^-1·h。盐酸小檗碱口服给药的药时曲线符合二室开放模型,主要药动学参数分别为：t1／2α为（1．87±0．76）h,t1／2β为（4．18±3.14）h,t1／2ka为（0．89±0．46）h,Tmax为（2．64±0．63）h,Cmax为（4．09±0．11）μg·L^-1,AUC为（26．18±10．73）μg·L^-1·h,绝对生物利用度为2．03％。鸡口服盐酸小檗碱的生物利用度低,消除较快。     

Pharmacokinetic analysis of cefquinome in healthy chickens

1. The pharmacokinetics of cefquinome (CEQ) in chickens was determined after intravenous (IV) and intramuscular (IM) administration of 2?mg/kg body weight. Plasma concentrations were measured by high performance liquid chromatography assay with an ultraviolet detector at 265?nm wavelength.

2. Plasma concentration–time data after IV administration were best fitted by a two-compartment model. The pharmacokinetic parameters following IV injection were distribution half-life 0·43?±?0·19?h, elimination half-life 1·29?±?0·10?h, total body clearance 0·35?±?0·04?l/kg/h, area under curve 5·33?±?0·55?µg/h/ml and volume of distribution at steady state 0·49?±?0·05?l/kg.

3. Plasma concentration–time data after IM administration were best described by a two-compartment model. The pharmacokinetic parameters after IM administration were absorption half-life 0·07?±?0·02?h, distribution half-life 0·58?±?0·27?h, elimination half-life 1·35?±?0·20?h, peak concentration 3·04?±?0·71?µg/ml and bioavailability 95·81?±?5·81%.

4. Cefquinome kinetics in chicken and data from other species were summarised and analysed to provide a comprehensive understanding of CEQ pharmacokinetics.     

Pharmacokinetic variables and tissue residues of enrofloxacin and ciprofloxacin in healthy pigs

OBJECTIVES: To determine pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after a single i.v. and i.m. administration of enrofloxacin and tissue residues after serial daily i.m. administration of enrofloxacin in pigs. ANIMALS: 20 healthy male pigs. PROCEDURE: 8 pigs were used in a crossover design to investigate pharmacokinetics of enrofloxacin after a single i.v. and i.m. administration (2.5 mg/kg of body weight). Twelve pigs were used to study tissue residues; they were given daily doses of enrofloxacin (2.5 mg/kg, i.m. for 3 days). Plasma and tissue concentrations of enrofloxacin and ciprofloxacin were determined. Residues of enrofloxacin and ciprofloxacin were measured in fat, kidney, liver, and muscle. RESULTS: Mean (+/-SD) elimination half-life and mean residence time of enrofloxacin in plasma were 9.64+/-1.49 and 12.77+/-2.15 hours, respectively, after i.v. administration and 12.06+/-0.68 and 17.15+/-1.04 hours, respectively, after i.m. administration. Half-life at alpha phase of enrofloxacin was 0.23+/-0.05 and 1.94+/-0.70 hours for i.v. and i.m. administration, respectively. Maximal plasma concentration was 1.17 +/-0.23 microg/ml, and interval from injection until maximum concentration was 1.81+/-0.23 hours. Renal and hepatic concentrations of enrofloxacin (0.012 to 0.017 microg/g) persisted for 10 days; however, at that time, ciprofloxacin residues were not detected in other tissues. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered i.m. at a dosage of 2.5 mg/kg for 3 successive days, with a withdrawal time of 10 days, resulted in a sum of concentrations of enrofloxacin and ciprofloxacin that were less than the European Union maximal residue limit of 30 ng/g in edible tissues.     

Mutant-prevention concentrations of enrofloxacin for Escherichia coli isolates from chickens

OBJECTIVE: To investigate the development of enrofloxacin resistance among Escherichia coli isolates obtained from chickens by determining mutant-prevention concentrations (MPCs) and sequence the quinolone resistance-determining regions (QRDRs) of gyrA and parC genes in selected isolates. SAMPLE POPULATION: 15 chicken-derived E coli isolates. PROCEDURES: For all isolates, MPC and minimal inhibition concentration (MIC) of enrofloxacin were determined. The MPCs and maximum serum drug concentrations attained with enrofloxacin doses recommended for treatment of E coli infections in chickens were compared. Mutation frequencies and QRDR sequence changes in gyrA and parC were also determined. RESULTS: In 2 of 15 E coli strains, MPCs were low (0.016 and 0.062 microg/mL), MPC:MIC ratios were 2 and 4, and the GyrA and ParC proteins had no mutations. In 9 susceptible isolates with a GyrA point mutation, MPCs ranged from 2 to 16 microg/mL. For isolates with double mutations in GyrA and a single mutation in ParC, MPCs were > 32 microg/mL (several fold greater than the maximal plasma concentration of enrofloxacin in chickens); mutation frequencies were also much lower, compared with frequencies for single-mutation isolates. CONCLUSIONS AND CLINICAL RELEVANCE: For E coli infections of chickens, MPC appears to be useful for determining enrofloxacin-dosing strategies. The high MPC:MIC ratio may result in enrofloxacin-treatment failure in chickens infected with some wild-type gyrA E coli isolates despite the isolates' enrofloxacin susceptibility (MICs 0.125 to 1 microg/mL). For infections involving isolates with high MPCs, especially those containing mutations in gyrA and parC genes, treatment with combinations of antimicrobials should be adopted.     

Pharmacokinetic behaviour of enrofloxacin in greater rheas following a single-dose intramuscular administration

The pharmacokinetic behaviour of enrofloxacin in greater rheas was investigated after intramuscular (IM) administration of 15 mg/kg. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by high performance liquid chromatography. Enrofloxacin peak plasma concentration (C(max)=3.30+/-0.90 microg/mL) was reached at 24.17+/-9.17 min. The terminal half-life (t(1/2lambda)) and area under the curve (AUC) were 2.85+/-0.54 h and 4.18+/-0.69 microg h/mL, respectively. The AUC and C(max) for ciprofloxacin were 0.25+/-0.06 microg/mL and 0.66+/-0.16 microg h/mL, respectively. Taking into account the values obtained for the efficacy indices, an IM dose of 15 mg/kg of enrofloxacin would appear to be adequate for treating infections caused by highly susceptible bacteria (MIC(90)<0.03 microg/mL) in greater rheas.     

恩诺沙星在鸡内服和肌肉注射给药后的排泄研究

恩诺沙星是动物专用的氟喹诺酮类药物。动物内服和注射恩诺沙星后，部分在肝脏脱乙基，代谢为环丙沙星，主要经肾排泄，也有一部分经胆汁排泄。本文旨在研究鸡给予恩诺沙星后，原形和活性代谢产物环丙沙星的排泄规律，为研究合理用药、制订畜禽养殖业污物排放标准及兽药的环境风险评估等提供科学依据。     

Pharmacokinetic behaviour of enrofloxacin and its metabolite ciprofloxacin after subcutaneous administration in cattle

This study compared pharmacokinetic profiles in cattle dosed subcutaneously with two different formulations of enrofloxacin (5% and 10%) at a dose of 5 mg/kg. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by a HPLC/u.v. method. The pharmacokinetic parameters of enrofloxacin and its metabolite were similar in both injectable formulations. Enrofloxacin peak plasma concentration (5%: 0.73 ± 0.32; 10%: 0.60 ± 0.14 μg/mL) was reached at 1.21 ± 0.52 and 1.38 ± 0.52 h to 5 and 10%, respectively. The terminal half-live and area under curve were 2.34 ± 0.46 and 2.59 ± 0.46 h, and 3.09 ± 0.81 and 2.93 ± 0.58 μg·h/mL, to 5 and 10%, respectively. The AUC/MIC₉₀ and Cmax/MIC₉₀ ratios for both formulations exceed the proposed threshold values for optimized efficacy and minimized resistance development whilst treating infections or septicaemia caused by P. multocida and E. coli.     

Pharmacokinetic profile and tissue distribution of monensin in broiler chickens

1. The pharmacokinetics of monensin, including half‐life, apparent volume of distribution, total body clearance, systemic bio‐availability and tissue residues were determined in broiler chickens. The drug was given by intracrop and intravenous routes in a single dose of 40 mg/kg body weight.

2. Following intravenous injection the kinetic disposition of monensin followed a two compartments open model with absorption half life of 0.59 h, volume of distribution of 4.11 I/kg and total body clearance of 28.36 ml/kg/min. The highest serum concentrations of monensin were reached 0.5 h after intracrop dosage with an absorption half‐life of 0.27 h and an elimination half life of 2.11 h. The systemic bioavailability was 65.1% after intracorp administration. Serum protein‐binding tendency of monensin calculated in vitro was 22.8%.

3. Monensin concentrations in the serum and tissues of chickens after a single intracrop dose of pure monensin (40 mg/kg body weight) were higher than those after feeding a supplemented monensin pre‐mix (120 mg/kg) for 2 weeks. Monensin residues were detected in tested body tissues, collected 2, 4, 6 and 8 h after oral administration. The highest conentration was found in the liver. In addition, monensin residues were detected only in liver, kidney and fat 24 h after the last oral dose. No monensin residues could be detected in tissues after 48 h, except in liver which cleared completely by 72 h.     

Persistence of Mycoplasma gallisepticum in chickens after treatment with enrofloxacin without development of resistance

The ability of the avian pathogen Mycoplasma gallisepticum to persist despite fluoroquinolone treatment was investigated in chickens. Groups of specific pathogen free chickens were experimentally infected with M. gallisepticum and treated with enrofloxacin at increasing concentrations up to the therapeutic dose. When M. gallisepticum could no longer be re-isolated from chickens, birds were stressed by inoculation of infectious bronchitis virus or avian pneumovirus. Although M. gallisepticum could not be cultured from tracheal swabs collected on several consecutive sampling days after the end of the enrofloxacin treatments, the infection was not eradicated. Viral infections reactivated the mycoplasma infection. Mycoplasmas were isolated from tracheal rings cultured for several days, suggesting that M. gallisepticum persisted in the trachea despite the enrofloxacin treatment. The minimal inhibitory concentration (MIC) of enrofloxacin for most of the re-isolated mycoplasmas was the same as that of the strain with which the birds were inoculated. Furthermore, no mutation could be detected in the fluoroquinolone target genes. These results suggest that M. gallisepticum can persist in chickens without development of resistance despite several treatments with enrofloxacin.     

Physicochemical characterization and pharmacokinetics in broiler chickens of a new recrystallized enrofloxacin hydrochloride dihydrate

Enrofloxacin, a key antimicrobial agent in commercial avian medicine, has limited bioavailability (60%). This prompted its chemical manipulation to yield a new solvate‐recrystallized enrofloxacin hydrochloride dihydrate entity (enro_C). Its chemical structure was characterized by means of mass spectroscopy, Fourier transformed infrared spectroscopy, X‐ray powder diffraction, and thermal analysis. Comparative oral pharmacokinetics (PK) of reference enrofloxacin (enro_R) and enro_C in broiler chickens after oral administration revealed noticeable improvements in key parameters and PK/PD ratios. Maximum serum concentration values were 2.61 ± 0.21 and 5.9 ± 0.42 μg/mL for enro_R and enro_C, respectively; mean residence time was increased from 5.50 ± 0.26 h to 6.20 ± 0.71 h and the relative bioavailability of enro_C was 336%. Considering C_max/MIC and AUC/MIC ratios and the MIC values for a wild‐type Escherichia coli O78/H12 (0.25 μg/mL), optimal ratios will only be achieved by enro_C (C_max/MIC = 23.6 and AUC/MIC = 197.7 for enro_C; vs. C_max/MIC = 10.4 and AUC/MIC = 78.1 for enro_R). Furthermore, enro_C may provide in most cases mutant prevention concentrations (C_max/MIC ≥ 16). Ready solubility of powder enro_C in drinking water at concentrations regularly used (0.01%) to provide an additional advantage of enro_C in the field. Further development of enro_C is warranted before it can be recommended for clinical use in veterinary medicine.     

Pharmacokinetic changes of several antibiotics in chickens during induced fatty liver

The concentrations of five antibiotics (erythromycin, lincomycin, penicillin G, streptomycin and oxytetracycline) were determined in chicken serum before and after induced fatty liver. The pharmacokinetic variables were calculated according to the obtained data. The crossover trial design involved 10 chickens for each antibiotic. The fatty liver was produced by oestradiol-dipropionate injections and monitored by serum malic enzyme activity determinations. Protein binding of the respective antibiotics was determined in vitro in the serum obtained from normal and oestrogen-treated birds. Induction of fatty liver caused several changes in the determined variables. The measured peak concentrations were higher for lincomycin and erythromycin and lower for penicillin and oxytetracycline while streptomycin remained unchanged. The peak concentration of streptomycin appeared earlier and the peak of oxytetracycline later than in the normal chickens. The elimination half-lives were shorter for erythromycin, lincomycin and streptomycin and increased for penicillin and oxytetracycline. The area under the concentration curve (AUC) decreased for erythromycin, penicillin and streptomycin, increased for oxytetracycline and remained unchanged for lincomycin. The body clearance (ClB/f) and the apparent specific volume of distribution (Vd(area'/f) were considerably changed in association with fatty liver induction. Since the fraction of the drug absorbed (f) is not known, it can only be speculated that changes in distribution rather than reduced liver function altered the kinetics. The protein binding was decreased for all the antibiotics, but this did not seem to be the reason for changes in kinetics, except perhaps in the case of penicillin.