Comparative pharmacokinetics of enrofloxacin and tissue concentrations of parent drug and ciprofloxacin after intramuscular administrations of free and liposome-encapsulated enrofloxacin in rabbits

Pharmacokinetic properties and tissue concentrations of enrofloxacin and ciprofloxacin were compared after intramuscular (i.m.) administrations of free and liposome-encapsulated enrofloxacin at the dose of 5 mg/kg body weight (bw). Twelve healthy adult New Zealand white rabbits were used in the experiment. Blood samples were obtained at 10, 20, 40, 60 and 90 min and 2, 4, 6, 8 and 12 h and tissue samples were collected 24 h after injection. Concentrations of drugs in serum were determined by high-performance liquid chromatography. Pharmacokinetics were best described by a two-compartment open model. Results indicated that absorption rate was slow, peak concentration was higher (P < 0.05), and the time to peak concentration (tmax congruent with 1.5 h) was significantly longer (P < 0.05) for liposome-encapsulated enrofloxacin (LEE) when compared with free enrofloxacin. Values of elimination half-life (t1/2beta = 12.9 h) and mean residence time (MRT = 17.6 h) of liposome-encapsulated enrofloxacin were longer (P < 0.05) and total clearance (Cl = 0.43 l/h/kg) was lower than those of free form. Moreover, the distribution volume at steady-state (Vd(ss) = 14.4 l/kg) of enrofloxacin administered encapsulated into liposomes was significantly higher (P < 0.05) than that of free enrofloxacin (FE). The tissue levels of enrofloxacin and ciprofloxacin after LEE injection were not different (P > 0.05) from FE. In conclusion, the result of present study suggest that LEE may be a beneficial and valuable formulation in the treatment of infectious diseases caused by sensitive pathogens in animals, providing sustained drug release from injection side and prolonged therapeutic serum concentrations after i.m. administration.     

Evaluation of the morantel sustained release bolus in cows and calves

The efficacy of the morantel sustained release bolus (MSRB) in controlling gastrointestinal parasitism in beef cattle was assessed during the 1982 spring-autumn grazing season. Forty-eight cows and their calves were allotted to three equal groups. One group (T-1) served as a nonmedicated control group. One MSRB was administered to each calf of the T-2 group, and to each cow and calf of the T-3 group at the beginning of the study. The efficacy of the bolus was assessed by comparison of weight gain performance and parasitological data (fecal worm egg counts, herbage larval counts, worm counts from tracer and principal trial calves, and plasma pepsinogen level determinations). Though not statistically significant, treated calves from Group T-2 had a numerical mean weight gain advantage of 2.6 kg, and those from Group T-3 of 4.7 kg, over control calves. Average daily gains (ADG) for the three groups of calves were 0.69, 0.72, and 0.73 kg, respectively. Untreated cows from Group T-2 and treated cows from Group T-3 outperformed the control cows by 12.3 and 7.5 kg, respectively. Fecal worm egg counts from both groups of treated calves were significantly (P less than 0.01) lower than counts from control calves during the entire 169-day trial; notably, egg counts were reduced by 99% 28 days after MSRB administration to both groups of calves. There were no significant differences in the number of eggs counted from the three groups of cows, probably because of the very low numbers of eggs encountered. Mean total worm burdens of principal calves (six per group) necropsied at trial termination indicated a 91% (P less than 0.01) reduction in Group T-2 and an 87% reduction (P less than 0.01) in Group T-3. Worm-free tracer calves were introduced onto pastures every 28 days to monitor availability of infective larvae. The mean number of worms recovered at necropsy from tracer calves that grazed with control cattle increased as the season progressed. However, the numbers of parasites recovered each month from mid-August through mid-October from tracers that grazed pastures with treated cattle were lower (P less than 0.05) than those levels displayed at trial initiation. In addition, the mean numbers of worms from treated group tracers were lower than from the controls for each necropsy period.(ABSTRACT TRUNCATED AT 400 WORDS)     

Self-mutilation in rabbits following intramuscular ketamine-xylazine-acepromazine injections

Following hind leg intramuscular injections of ketamine, xylazine, and acepromazine, 4 of 6 rabbits exhibited self-mutilation of the digits. At necropsy, the affected sciatic nerve appeared enlarged. Lymphohistiocytic perineural inflammation and fibrosis were observed, together with nerve degeneration. Neuronal regeneration as the reason for self-mutilation is discussed.     

Pharmacokinetics of enrofloxacin after intravenous and intramuscular injection in rabbits.

The pharmacokinetics and bioavailability of enrofloxacin were determined after IV and IM administration of 5 mg/kg of body weight to 6 healthy adult rabbits. Using nonlinear least-squares regression methods, data obtained were best described by a 2-compartment open model. After IV administration, a rapid distribution phase was followed by a slower elimination phase, with a half-life of 131.5 +/- 17.6 minutes. The mean body clearance rate was 22.8 +/- 6.8 ml/min/kg, and the mean volume of distribution was 3.4 +/- 0.9 L/kg. This large volume of distribution and the K12/K21 ratio close to 1, indicated that enrofloxacin was widely distributed in the body, but not retained in tissues. After a brief lag period (6.2 +/- 2.86 min), IM absorption was rapid (4.1 +/- 1.3 min) and almost complete. The mean extent of IM absorption was 92 +/- 11%, and maximal plasma concentration of 3.04 +/- 0.34 micrograms/ml was detected approximately 10 minutes after administration.     

Pharmacokinetics of enrofloxacin following intravenous and intramuscular administration in Angora rabbits

The pharmacokinetic behaviour and bioavailability of enrofloxacin (ENR) were determined after single intravenous (iv) and intramuscular (im) administrations of 5mg/kg bw to six healthy adult Angora rabbits. Plasma ENR concentrations were measured by high performance liquid chromatography. The pharmacokinetic data were best described by a two-compartment open model. ENR pharmacokinetic parameters were similar (p>0.05) for iv and im administrations in terms of AUC0-infinity, t1/2beta and MRT. ENR was rapidly (t1/2a, 0.05 h) and almost completely (F, 87%) absorbed after im injection. In conclusion, the pharmacokinetic properties of ENR following iv and im administration in Angora rabbits are similar to other rabbit breeds, and once or twice daily iv and im administrations of ENR at the dose of 5mg/kg bw, depending upon the causative pathogen and/or severity of disorders, may be useful in treatment of infectious diseases caused by sensitive pathogens in Angora rabbits.     

硫酸庆大霉素药剂学研究进展

本文以“庆大霉素”“制剂”“药物动力学”“Gentamycin”“preparation”“pharmacokinetics”为关键词,组合查询1988-2018年在中国知网、万方、维普、中国专利信息网、PubMed、Web of Science等国内外数据库中收录的相关文献,归纳、总结硫酸庆大霉素制剂学及药物动力学方面的研究进展。结果表明:共检索到相关文献261篇,其中有效文献44篇。硫酸庆大霉素作为常用的氨基糖苷类药物之一,具有广泛的临床应用价值。目前,以硫酸庆大霉素作为单一主药上市的庆大霉素制剂多为注射途径给药制剂与普通口服制剂。缓控迟释制剂、经皮给药制剂等近年来发展迅速,逐步成为硫酸庆大霉素制剂研发的重点,为硫酸庆大霉素制剂研发开辟了新的思路。     

Tissue disposition of azithromycin after intravenous and intramuscular administration to rabbits

Tissue disposition of azithromycin after intravenous (IV) or intramuscular (IM) injection at a single dose rate of 10mg/kg bodyweight were investigated in rabbits using a modified agar diffusion bioassay for determining tissue concentrations. The pharmacokinetic behaviour of azithromycin was characterized by low and sustained plasma concentrations but high and persistent tissue concentrations. Kinetic parameters indicated a high retention of the drug in peripheral compartments. The plasma half-lives after IV and IM administrations were similar being 21.8h and 23.1h, respectively, while the half-lives obtained in tissues after IV and IM administration were at least 1.4 and 1.9 times longer than in plasma, respectively. The highest tissue concentrations were found in bile, liver and spleen whereas the lowest ones were found in skeletal muscle (although they were higher than those in plasma). From the results of the single administration in this study an IM dosage regimen can be proposed that achieves minimum concentrations over 2mg/L in rabbits: three doses of 4-5mg/kg/day would provide suitable therapeutic concentrations in pulmonary tissues over seven days.     

Pharmacokinetics and bioavailability of tildipirosin in rabbits following single-dose intravenous and intramuscular administration

The objective of this study was to determine the pharmacokinetics of tildipirosin in rabbits after a single intravenous (i.v.) and intramuscular (i.m.) injection at a dose of 4 mg/kg. Twelve white New Zealand rabbits were assigned to a randomized, parallel trial design. Blood samples were collected prior to administration and up to 14 days postadministration. Plasma concentrations of tildipirosin were quantified using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The pharmacokinetic parameters were calculated using a noncompartmental model in WinNonlin 5.2 software. Following i.v. and i.m. administration, the elimination half-life (T_1/2λ) was 81.17 ± 9.28 and 96.68 ± 15.37 hr, respectively, and the mean residence time (MRT_last) was 65.44 ± 10.89 and 67.06 ± 10.49 hr, respectively. After i.v. injection, the plasma clearance rate (Cl) and volume of distribution at steady state (V_dss) were 0.28 ± 0.10 L kg^-1 h⁻¹ and 17.78 ± 5.15 L/kg, respectively. The maximum plasma concentration (C_max) and time to reach maximum plasma concentration (T_max) after i.m. administration were 836.2 ± 117.9 ng/ml and 0.33 ± 0.17 hr, respectively. The absolute bioavailability of i.m. administration was 105.4%. Tildipirosin shows favorable pharmacokinetic characteristics in rabbits, with fast absorption, extensive distribution, and high bioavailability. These findings suggest that tildipirosin might be a potential drug for the prevention and treatment of respiratory diseases in rabbits.     

Pharmacokinetic-pharmacodynamic integration of orbifloxacin in rabbits after intravenous, subcutaneous and intramuscular administration

The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits (n=6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration-time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution (V(ss)) and total body clearance (Cl) of orbifloxacin after i.v. administration were estimated to be 1.71+/-0.38 L/kg and 0.91+/-0.20 L/h x kg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95+/-0.82 and 3.24+/-1.33 mg/L at 0.67+/-0.20 and 0.65+/-0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67+/-11.02% and 109.87+/-8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC/MIC and C(max)/MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations.     

Pharmacokinetics and tissue tolerance of azithromycin after intramuscular administration to rabbits

The pharmacokinetics of azithromycin after intravenous and intramuscular injection at a single dose rate of 10mg/kg bodyweight were investigated in rabbits by using a modified agar diffusion bioassay for determining plasma concentrations. The plasma creatine kinase activity was determined after i.m. administration for the evaluation of the tissue tolerance. The elimination half-lives of azithromycin after intravenous and intramuscular administration were 24.1 and 25.1h, respectively. After intramuscular administration mean peak plasma concentration was 0.26+/-0.01 mg/L and bioavailability was 97.7%. Plasma CK activity rose sharply within 8h after i.m. injection of azithromycin; activity returned to pre-treatment level by 48-72 h post-treatment. The transient rise in serum CK activity indicates some degree of muscle tissue damage at the injection site.     

Pharmacokinetics of florfenicol after intravenous and intramuscular administration in New Zealand White rabbits

The pharmacokinetic disposition and bioavailability of florfenicol (FF) were determined after single intravenous (i.v.) and intramuscular (i.m.) administrations of 25 mg/kg b.w. to ten healthy New Zealand White rabbits. Plasma FF concentrations were determined by high-performance liquid chromatography (HPLC). The plasma pharmacokinetic values for FF were best described by a one-compartment open model. The elimination half-life (t_1/2β) was different (p < 0.05) however, the area under curve (AUC) was similar (p > 0.05) after i.v. and i.m. administrations. FF was rapidly eliminated (t_1/2β 1.49 ± 0.23 h), slowly absorbed and high (F, 88.75 ± 0.22%) after i.m. injection. In addition, FF was widely distributed to the body tissues (V_ss 0.98 ± 0.05 L/kg) after i.v. injection. In this study the time that plasma concentration exceeded the concentration of 2 μg/mL was approximately 6 h. For bacteria with MIC of 2 μg/mL, frequent administration at this dose would be needed to maintain the concentration above the MIC. However, it is possible that rabbit pathogens may have MIC values less than 2 μg/mL which would allow for less frequent administration. Further studies are necessary to identify the range of MIC values for rabbit pathogens and to identify the most appropriate PK-PD parameter needed to predict an effective dose.     

Evaluation of the morantel sustained release trilaminate in the control of parasitic gastroenteritis in first season grazing cattle

A novel intraruminal bolus developed for the sustained delivery of the anthelmintic morantel tartrate was evaluated in the seasonal control of parasitic gastroenteritis in first season grazing calves. The morantel sustained release trilaminate is a trilaminate sheet consisting of a central lamina of a morantel tartrate/ethylene vinyl acetate matrix coated on both sides with a thin impermeable layer of ethylene vinyl acetate. A symmetrical pattern of circular perforations punched through the device controls the release of morantel. Administration of the trilaminate to calves significantly reduced their faecal egg output compared with untreated controls and thus reduced pasture larval contamination. Clinical parasitic gastroenteritis was prevented in the treated calves and there were significant reductions in their worm burdens compared with the untreated control calves both during and at the end of the grazing season. The control of parasitic gastroenteritis resulted in a significantly greater (P less than 0.0001) weight gain, of 45 kg, by the treated calves.     

Pharmacokinetic-pharmacodynamic integration of moxifloxacin in rabbits after intravenous, intramuscular and oral administration

The pharmacokinetics of moxifloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and oral dose of 5 mg/kg to healthy white New Zealand rabbits (n = 6). Moxifloxacin concentrations were determined by HPLC assay with fluorescence detection. The moxifloxacin plasma concentration vs. time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and orally administered moxifloxacin was best described by a one-compartment model. The plasma moxifloxacin clearance (Cl) for the i.v route was (mean +/- SD) 0.80 +/- 0.02 L/h.kg. The steady-state volume of distribution (Vss) was 1.95 +/- 0.18 L/kg. The terminal half-life (t(1/2lambdaz)) was (mean +/- SD) 1.84 +/- 0.12, 2.09 +/- 0.05 and 2.15 +/- 0.07 h after i.v., i.m. and oral, respectively. Minimal inhibitory concentration (MIC) assays of moxifloxacin against different strains of S. aureus were performed in order to compute pharmacodynamic surrogate markers. From these data, it is concluded that a 5 mg/kg dose moxifloxacin would be effective by i.m. and oral routes in rabbits against bacterial isolates with MIC < or = 0.06 microg/mL and possibly for MIC < or = 0.12 microg/mL, but in the latter case a higher dose would be required.     

Determination of intracellular concentrations of free and two types of liposome-encapsulated enrofloxacin in anatolian shepherd dog monocytes

In this study, it was evaluated the accumulation of free and two types of liposome-encapsulated enrofloxacin (LEE) at the doses of 0.25, 0.5 and 1 microg/ml, which were clinically relevant concentrations into monocytes of healthy Anatolian shepherd dogs. Enrofloxacin was encapsulated with two different types of liposome in multilamellar large vesicles (MLV). Type A MLV composed of 15 mg egg phosphatidylcholine and 35 mg cholesterol, Type B MLV composed of phosphatidylcholine (PC), cholesterol and enrofloxacin, in a molar ratio of 1 : 1 : 1. The mean sizes of Type A and Type B liposome were found to be 7.65 and 4.27 microm, respectively. However, the mean encapsulation rate determined of Type A (13 +/- 2%) was found lower than Type B liposome (44 +/- 3%). The amounts of intracellular enrofloxacin concentrations were determined by high performance liquid chromatography. Type B LEE accumulated significantly higher level into monocytes when compared to free drug or Type A liposome. This study showed that Type B LEE markedly concentrated within monocytes and may improve the antibacterial efficacy of the antibiotic.     

Pharmacokinetics of norfloxacin after intravenous,intramuscular and subcutaneous administration to rabbits

The disposition kinetics of norfloxacin, after intravenous, intramuscular and subcutaneous administration was determined in rabbits at a single dose of 10 mg/kg. Six New Zealand white rabbits of both sexes were treated with aqueous solution of norfloxacin (2%). A cross‐over design was used in three phases (2 × 2 × 2), with two washout periods of 15 days. Plasma samples were collected up to 72 hr after treatment, snap‐frozen at ?45°C and analysed for norfloxacin concentrations using high‐performance liquid chromatography. The terminal half‐life for i.v., i.m. and s.c. routes was 3.18, 4.90 and 4.16 hr, respectively. Clearance value after i.v. dosing was 0.80 L/h·kg. After i.m. administration, the absolute bioavailability was (mean ± SD ) 108.25 ± 12.98% and the C_max was 3.68 mg/L. After s.c. administration, the absolute bioavailability was (mean ± SD ) 84.08 ± 10.36% and the C_max was 4.28 mg/L. As general adverse reactions were not observed in any rabbit and favourable pharmacokinetics were found, norfloxacin at 10 mg/kg after i.m. and s.c. dose could be effective in rabbits against micro‐organisms with MIC ≤0.14 or 0.11 μg/mL , respectively.     

Evaluation of dirlotapide for sustained weight loss in overweight Labrador retrievers

The effects of dirlotapide on body weight (BW) reduction were investigated in overweight Labradors in two parallel-design studies. Study A involved 42 dogs randomized to 0.0, 0.025, 0.05, 0.1, 0.2 or 0.4 mg dirlotapide/kg/day orally for 4 weeks. Study B involved 72 dogs randomized to nine treatments: placebo (24 weeks); dirlotapide (24 weeks) followed by placebo (28 weeks); or dirlotapide (52 weeks); on diets containing 5%, 10% or 15% fat. Dirlotapide dose (initially 0.1 mg/kg) was adjusted monthly during 24-week weight-loss and subsequent 28-week weight-stabilization phases. Food was offered above maintenance energy requirements (MER× 1.1–1.2) based on initial BW. Body composition (body fat, lean tissue and bone mineral content) was monitored using dual-energy X-ray absorptiometry. After treatment, dogs that had received dirlotapide for 52 weeks were fed 90% of quantity consumed at week 52. In study A, BW and food intake decreased asymptotically with dose: mean weekly weight loss exceeded 1% at 0.1–0.4 mg/kg. In study B, dirlotapide resulted in significant mean weekly weight loss (>0.8%) and decreased food intake over 24 weeks compared with placebo ( P  = 0.0001) for all diets. Food restriction minimized post-treatment weight rebound. Dirlotapide administered daily to dogs for up to 52 weeks was clinically safe and resulted in sustained weight reduction.     

Pharmacokinetic-pharmacodynamic integration of danofloxacin after intravenous, intramuscular and subcutaneous administration to rabbits

The pharmacokinetics of danofloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 6 mg/kg to healthy rabbits. Danofloxacin concentration were determined by high-performance liquid chromatography assay with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of danofloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The danofloxacin plasma concentration versus time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and subcutaneously administered danofloxacin was best described by a one-compartment model. The terminal half-life for i.v., i.m. and s.c. routes was 4.88, 6.70 and 8.20 h, respectively. Clearance value after i.v. dosing was 0.76 L/kg.h. After i.m. administration, the absolute bioavailability was mean (+/-SD) 102.34 +/- 5.17% and the Cmax was 1.87 mg/L. After s.c. administration, the absolute bioavailability was mean (+/-SD) 96.44 +/- 5.95% and the Cmax was 1.79 mg/L. Danofloxacin shows a favourable pharmacokinetics profile in rabbits reflected by parameters such as a long half-life and a high bioavailability. However, in consideration of the low AUC/MIC indices obtained, its use by i.m. and s.c. route against the S. aureus strains assayed in this study cannot be recommended given the risk for selection of first mutant subpopulations.