Pharmacokinetics, milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin, after intravenous and intramuscular administration to lactating goats.

The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady-state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady-state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance. The study was carried out with six healthy, female, adult Anglo Nubian lactating goats. Marbofloxacin was administered at 5 mg/kg bw by IV and IM route. Serum and milk concentrations of MFX were determined with HPLC/uv. From 106 regional strains of CNS isolated from caprine mastitis in herds from Córdoba, Argentina, MICs and MPCs were determined. MIC90 and MPC90 were 0.4 and 6.4 µg/ml, respectively. MIC and MPC-based PK/PD analysis by Monte Carlo simulation indicates that IV and IM administration of MFX in lactating goats may not be adequate to recommend it as an empirical therapy against CNS, because the most exigent endpoints were not reached. Moreover, this dose regimen could increase the probability of selecting mutants and resulting in emergence of resistance. Based on the results of Monte Carlo simulation, the optimal dose of MFX to achieve an adequate antimicrobial efficacy should be 10 mg/kg, but it is important take into account that fluoroquinolones are substrates of efflux pumps, and this fact may determine that assumption of linear pharmacokinetics at high doses of MFX may be incorrect.

Pharmacokinetics of enrofloxacin after multiple subcutaneous and intramuscular administrations in adult ostriches.

1. The objective of the study was to evaluate the comparative pharmacokinetic behaviour of enrofloxacin in adult ostriches after single and multiple intramuscular (IM) and subcutaneous (SC) administrations. In addition, tissue tolerance was evaluated. 2. Enrofloxacin was well absorbed, but showed a short permanence after both administration routes. After multiple dose administrations the maximum and minimum peak plasma concentrations were very similar for both routes, obtaining a steady state phase from the second dose that extended until the last evaluated administration. 3. There was no significant accumulation after multiple IM or SC doses; however, there were differences in a fluctuation index after multiple intramuscular administrations that could be related to muscle damage. 4. The different microbiological efficacy indicators (PK/PD indices) obtained, the pharmacokinetic behaviour and CK serum concentrations suggest that subcutaneous enrofloxacin administration of 15 mg/kg every 12 h produce and maintain an efficient concentration of antibiotic that is a safer and more effective therapeutic option than intramuscular administration.

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 microg/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 microg x h/mL, to 5 and 10%, respectively. The AUC/MIC(90) and Cmax/MIC(90) 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.

Pharmacokinetics of a single intravenous dose of marbofloxacin in adult donkeys.

Six donkeys each received 2 mg/kg marbofloxacin as a 10 per cent aqueous solution administered intravenously. Principal pharmacokinetic parameters were determined and two efficacy indices were computed by using pharmacokinetic parameters and selected mic90 values of marbofloxacin against pathogenic equine strains to predict the efficacy of the drug at this dose. The pharmacokinetics of marbofloxacin in donkeys was characterised by a large mean volume of distribution at a steady state (1.15 [0.09] l/kg) and a long mean (sd) elimination half-life of 9.24 (1.96) hours. It was also characterised by a relatively slow total body clearance of 0.10 (0.02) l/kg/hour, slower than in horses. Using mic90 values of marbofloxacin against pathogenic equine strains with a daily dose of 2 mg/kg, appropriate values of efficacy indicators were obtained only for Enterobacteriaceae. Daily intravenous doses of 0.33, 2.62 and 20 mg/kg were calculated for evaluation in clinical trials of infections due to Enterobacteriaceae, Staphylococcus aureus and Streptococci, respectively.

Pharmacokinetics of enrofloxacin following intravenous administration to greater rheas: a preliminary study.

The pharmacokinetic behaviour of enrofloxacin (ENR) and its active metabolite ciprofloxacin (CIP) were determined in six greater rheas following a single intravenous (i.v.) dose of 15 mg/kg bw. Plasma concentrations of ENR and CIP were simultaneously determined by a HPLC/u.v. method. Following i.v. administration, the plasma drug concentrations were best fitted by an open two-compartment model with a rapid distribution phase. The high volume of distribution (V(ss)=5.01 L/Kg) suggests good tissue penetration. ENR presents a high clearance (3.95 L/kg h) explaining the low AUC values (3.57 mg h/L) and a short permanence (t(1/2beta)=2.66 h and MRT=1.23 h). Ciprofloxacin comprised 14% of the total fluoroquinolone (ENR+CIP).

Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration.

The pharmacokinetic behaviour of marbofloxacin, a new fluoroquinolone antimicrobial agent developed exclusively for veterinary use, was studied in mature horses (n = 5) after single-dose i.v. and i.m. administrations of 2 mg/kg bwt. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and data obtained were subjected to compartmental and noncompartmental kinetic analysis. This compound presents a relatively high volume of distribution (V(SS) = 1.17 +/- 0.18 l/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.19 +/- 0.042 l/kgh, which is related to a long elimination half-life (t(1/2beta) = 4.74 +/- 0.8 h and 5.47 +/- 1.33 h i.v. and i.m. respectively). Marbofloxacin was rapidly absorbed after i.m. administration (MAT = 33.8 +/- 14.2 min) and presented high bioavailability (F = 87.9 +/- 6.0%). Pharmacokinetic parameters are not significantly different between both routes of administration (P>0.05). After marbofloxacin i.m. administration, no adverse reactions at the site of injection were observed. Serum CK activity levels 12 h after administration increased over 8-fold (range 3-15) compared with pre-injection levels, but this activity decreased to 3-fold during the 24 h follow-up period. Based on the value of surrogate markers to predict clinical success, Cmax/MIC ratio or AUC/MIC ratio, single daily marbofloxacin dose of 2 mg/kg bwt may not be effective in treating infections in horses caused by pathogens with an MIC > or = 0.25 microg/ml. However, if we use a classical antimicrobial efficacy criteria, marbofloxacin can reach a high plasma peak concentration and maintain concentrations higher than MICs determined for marbofloxacin against most gram-negative veterinary pathogens throughout the administration period. Taking into account the fact that fluoroquinolones are considered to have a concentration-dependent effect and a long postantibiotic effect against gram-negative bacteria, a dose of 2 mg/kg bwt every 24 h could be adequate for marbofloxacin in horses.

Ivermectin residue depletion in food producing species and its presence in animal foodstuffs with a view to human safety.

From a human safety perspective, the administration of ivermectin to food producing animal species entails potential risks related to the presence of drug residues in edible tissues, milk, and other derived products. The European Medicines Agency has established the maximum residue limits for ivermectin in the European Union, with values of 100 µg·kg(-1) in fat and liver and 30 µg·kg(-1) in kidney for all mammalian food producing species, in order to ensure that the amount of ivermectin that can be found in animal foodstuff is below dangerous levels for the consumers. According to these values, withdrawal periods after subcutaneous injection were recently established in the European Union (2009), in 49 days for products containing ivermectin as a single active substance or in combination with closantel, and in 66 days when combined with clorsulon. The marker residue for ivermectin was found to be H(2)B(1a), which is the major component of the parent compound. The tissue distribution of residues and the overall ratios of marker to total residues were generally similar in most species, and the highest concentrations of ivermectin residues were found in fat and liver with high levels also detected in injection site muscles. Ivermectin is not licensed for use in animals from which milk is produced for human consumption, however its extra-label use should be considered regarding human safety, due to its long persistence in milk and milk-derived products.

Pharmacokinetics of intramuscular ketamine in young ostriches premedicated with romifidine.

Ketamine is a short-acting dissociative anaesthetic for chemical restraint and surgical anaesthesia in domestic and non-domestic animals. The present study was designed to determine the pharmacokinetics of a single dose of ketamine (10 mg/kg) after intramuscular (i.m.) administration to young ostriches premedicated with romifidine. Ketamine was rapidly absorbed after i.m. administration. Maximal ketamine concentration (C(max)) of 2.93 +/- 0.61 microg/ml was reached at 12.5 +/- 2.50 min and thereafter ketamine concentrations decreased rapidly. The elimination half-life (t(1/2 z)) obtained was 62.37 +/- 17.37 min and mean residence time (MRT) was 77.33 +/- 19.12 min. The area under the curve (AUC) was 114.19 +/- 15.76 microg x min/ml.

[Measurement of spontaneous motility in vitro of the cervical ring in sheep]. / Registro de la motilidad espontánea in vitro de los anillos de cervix de óvidos.

Spontaneous motility has been observed within in vitro preparations by different annulars of the cervix, as well as the characteristics shown this structure. This motor activity is cyclic, amplitude and tone not changing from some annulars to others, working on two grammes tension, but frequency and rhythm show large changes, altering the frequency from 7.3 contractions to minute in the first annular to 4.05 in the fifth annular. However, there appears denticulate peaks, with an incidence of 11% in the first annular, growing to 100% in the fifth annular.

[Measurement of the spontaneous motility in vitro of the floor of the reticular sulcus in cattle]. / Registro de la motilidad espontánea in vitro del suelo de la gotera reticular en bóvidos.

The bases and the parameters which define the smooth muscle spontaneous motility of the reticular groove floor in cattle have been established. The study has been carried out in 27 esophageal grooves in a classic organ bath technique. The results show a recognizable own spontaneous motility with two kinds of contractions: high tension ones and others with smaller contraction intensity. The young animal parameter values are different from those of grown-up ones. In adults, these values depend on the muscular dissection belt.

Age-related changes in the pharmacokinetics of marbofloxacin after intravenous administration in goats.

The pharmacokinetics of marbofloxacin was studied in adult goats and 1-, 3- and 6-weeks-old kids after single dose i.v. dose of 2 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography (HPLC) and the data collected were subjected to compartmental kinetic analysis. Volume of distribution was relatively high in adult goats (Vss = 1.31 L/kg), and increased with age (Vss = 0.92 L/kg, 0.95 L/kg and 1.00 L/kg, in 1-, 3- and 6-weeks-old kids respectively). Total body clearance (Cl) also increased with age from 0.080 L/kg.h (1-week-old) to 0.097 L/kg.h (3-weeks-old), 0.18 L/kg.h (6-weeks-old) and 0.23 L/kg.h (adult goats). As a consequence of increased body Cl, area under the plasma concentration vs. time curve decreased with age (AUC = 27.46 microg.h/mL, 22.61 microg.h/mL, 11.86 microg.h/mL and 8.44 microg.h/mL in 1-, 3-, 6-weeks-old kids and adults, respectively) and a longer elimination half-life was found during the first 3 weeks of age (t1/2beta = 9.66 h, 8.25 h, 6.44 h and 7.18 h, in 1-, 3-, 6-weeks-old kids and adults, respectively). Mean residence time decreased with age from 11.86 h in 1-week-old kids to 9.63 h (3 weeks), 5.76 h (6 weeks) and 5.06 h in adult goats.

Influence of Escherichia coli endotoxin-induced fever on the pharmacokinetic behavior of marbofloxacin after intravenous administration in goats.

The pharmacokinetic behavior of marbofloxacin was studied in seven healthy goats and in the same goats with induced fever after single-dose intravenous (i.v.) administration of 2 mg/kg b.w. Fever was induced by the administration of Escherichia coli endotoxin. Drug concentration in plasma was determined by high-performance liquid chromatography (HPLC). Drug distribution was somehow altered by fever as febrile goats showed a volume of distribution at steady-state (Vss = 0.72 +/- 0.15 L/kg) lower than normal goats (Vss = 1.19 +/- 0.33 L/kg). The elimination of the drug was also modified. Total plasma clearance (Cl) decreased from 0.24 +/- 0.12 L/kg/h in healthy animals to 0.13 +/- 0.05 L/kg/h in animals with endotoxin-induced fever, which is related to an increase in the area under the plasma concentration-time curve (AUC). Consequently, mean residence time (MRT) was also slightly increased in sick animals (MRT = 5.28 +/- 00.99 and 6.09 +/- 01.45 h, in healthy and febrile animals, respectively).