J. O. Errecalde

Concentrations of danofloxacin 18% solution in plasma, milk and tissues after subcutaneous injection in dairy cows.

Danofloxacin is a fluoroquinolone developed for use in veterinary medicine. Its concentrations and pharmacokinetic profile in plasma, milk and tissues of lactating dairy cows were determined, and its milk withdrawal time (WT) calculated. Twenty-one dairy cows received a single subcutaneous administration of 18% mesylate danofloxacin salt (6 mgkg(-1)). Plasma and milk samples were obtained at different times until 48 h. Groups of three animals were sacrificed at different post-administration times and tissue samples (mammary gland, uterus, duodenum, jejunum, ileum, colon and mesenteric lymph nodes) obtained. Danofloxacin concentrations were determined by liquid chromatography with fluorescence detection. The milk WT was calculated by the Time to Safe Concentration method (Software WTM 1.4, EMEA). Danofloxacin was rapidly absorbed and its distribution from plasma to all sampled tissues and milk was extensive. Milk and tissues concentrations were several times above those found in plasma. Plasma area under the curve (AUCp) was 9.69 microghmL(-1) and its elimination half life (T(beta)(1/2)) was 12.53 h. AUC values for the various tissues and milk greatly exceeded AUCp. T(beta)(1/2) from milk and tissues ranged between 4.57 and 21.91 h and the milk withdrawal time was 73.48 h. The reported results support the potential use of danofloxacin in the treatment of mastitis and other infections in milk cows with 3 days of withdrawal.

The pharmacokinetics of thiamphenicol in lactating cows.

The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t1/2α) and elimination (t1/2β) half-lives of 6.10±1.39 min and 1.60±0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9±0.077 ml/kg per min and the apparent volume of distribution was 1220.79±256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t1/2P) (serum to quarters), was found to be 36.89±11.14 min. The equivalent elimination half-life (t1/2E) (quarters to serum) from the milk was 3.62±1.06 h and the peak thiamphenicol concentration in the milk was 23.09±3.42 µg/ml at 2.5±0.32 h.After intramuscular injection, the elimination half-life was 2.2±0.40 h, the absorption half-life was 4.02±1.72 min and the peak concentration in the serum was 30.90±5.24 µg/ml at 23±8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59±6.87 min, the elimination half-life was 5.91±4.97 h and the mean peak concentration in the milk was 17.37±2.20 µg/ml at 3.4±0.22 h.

Pharmacokinetics of Ricobendazole After its Intravenous, Intraruminal and Subcutaneous Administration in Sheep

Ricobendazole (RBZ) was administered in sheep at the dose rate of 5 mg/kg by intravenous (i.v.) route as a 10% experimental solution, by the intraruminal (i.r.) route as a 10% experimental suspension, and by the subcutaneous (s.c.) route as a 10% commercial formulation available in Argentina. Blood samples were drawn during a 60 h period. Plasma concentrations of RBZ and its inactive metabolite albendazole sulphone (ABZSO2) were determined by high-performance liquid chromatography. The pharmacokinetic parameters were determined by compartmental analysis. The fitting of the data was done by weighted least-squares non-linear regression analysis. The pharmacokinetic parameters were estimated for every animal by simultaneous fitting of the plasma concentrations profiles of RBZ obtained after its administration by the three routes. The kinetic analysis of ABZSO2 was performed by a statistical moment approach. Ricobendazole bioavailability was poor after i.r. administration, whereas high and sustained plasma concentrations and higher bioavailability were obtained after s.c. administration. A simple two-compartment open model explains in a mechanical sense the pharmacokinetic behaviour of RBZ in sheep and allows us to estimate the real first-order constant rate of absorption and the loss of drug from the absorption site after its administration by s.c. and i.r. routes.

Pharmacokinetics of azithromycin in lactating dairy cows with subclinical mastitis caused by Staphylococcus aureus.

Azithromycin is a time-dependent antimicrobial with long persistence. The main characteristics of azithromycin suggest that it could be useful for treating bovine mastitis caused by Staphylococcus aureus. To investigate this possibility, its pharmacokinetic (PK) behavior was studied. Six Holstein lactating cows with subclinical mastitis were administered two 10 mg/kg intramuscular (i.m.) doses of azithromycin, with a 48-h interval. Milk and plasma concentrations were measured by microbiological assay. The MIC(90) was determined in 51 S. aureus isolations to calculate pharmacokinetic/pharmacodynamic (PK/PD) parameters. Milk maximal concentration (C(max)) was 7.76 +/- 1.76 microg/mL (16.67 h post-first administration) and 7.82 +/- 2.18 microg/mL (14 h post-2(nd) administration). In plasma C(max) was 0.18 +/- 0.03 microg/mL (2 h post-1(rst) administration) and 0.11 +/- 0.03 microg/mL (14 h post-2(nd) administration). Azithromycin was eliminated from the milk with a half-life (T(1/2)lambda) of 158.26 +/- 137.7 h after 2(nd) administration, meanwhile plasma T(1/2)lambda resulted shorter(13.97 +/- 11.1 h). The mean area under the concentration vs. time curve from 0 to 24 h (AUC(0-24h)) was 153.82 +/- 34.66 microg.h/mL in milk secretion and 2.61 +/- 0.59 microgxh/mL in plasma. Infection presence in the quarters had a significant effect (P < 0.05) on the area under the concentration vs. time curve from 0 to infinity (AUC(0-infinity)) and clearance from the mammary gland (Cl(mam)/F). Moreover, it had influence on milk bioavailability (F(milk)), T(1/2)lambda, AUC(0-infinity) and mean residence time (MRT) in milk, which values resulted increased in mastitic quarters. In this study, it was determined that the production level and the mammary health status have an influence on PK parameters of azithromycin treatments in bovine mastitis.

The pharmacokinetics of a slow-release theophylline preparation in horses after intravenous and oral administration

The pharmacokinetics of a slow-release theophylline formulation was investigated following intravenous and oral administration at 10 mg/kg in horses. A tricompartmental model was selected to describe the intravenous plasma profile. The elimination half-life (t1/2β) was 16.91 ± 0.93 h, the apparent volume of distribution (Vd) was 1.35 ± 0.18 L/kg and the body clearance (ClB) was 0.061 ± 0.009 L kg−1 h. After oral administration the half-life of absorption was 1.24 ± 0.30 h, and the calculated bioavailability was above 100%. Thet1/2β after oral administration was 18.51 ± 1.75 h, only a little longer than that after intravenous administration. The slow release formulation did not exhibit any advantage in prolonging thet1/2β of theophylline in the horse.

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains.

The objective of this study was to evaluate the interaction of the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP) when combined with different families of antimicrobial agents against isogenic strains and multidrug-resistant (MDR) Escherichia coli field strains isolated from animals. Laboratory isogenic strains of E. coli with different levels of expression of efflux pumps were used as quality controls. Ten MDR E. coli strains were collected from healthy animals in a cross-sectional study in four commercial dairy farms. The MICs of florfenicol, ciprofloxacin, tetracycline and ampicillin were determined by a serial microdilution method in Luria-Bertani broth in the presence or absence of NMP. NMP used with ampicillin exerted no effect on the isogenic or field strains. In most of the field MDRE. coli strains and in an acrAB-overexpressing (AG112) isogenic strain, the MICs of florfenicol, ciprofloxacin and tetracycline decreased at least fourfold when the antimicrobial was combined with the highest NMP concentrations. In the wild-type strain (AG100), there were no decreases of more than twice the MIC, whilst in strain AG100A, an efflux pump-deficient strain, the MIC did not change, regardless of the concentration of NMP used with these three antimicrobials. Thus, ampicillin was not affected by the efflux pump mechanism, whereas ciprofloxacin, tetracycline and florfenicol were shown to be substrates of efflux pumps, with a consequent significant reduction in MICs. Resistance could not be completely reversed in the E. coli field strains by NMP, probably because other resistance mechanisms were also present. However, in strain AG112, the MIC results demonstrated that NMP expressed an important synergistic activity with florfenicol. The reduction in florfenicol MIC value was sufficient to reverse antimicrobial resistance completely for AG112.

Some Pharmacokinetic Parameters of Oxfendazole in Sheep

Soraci, A.L., Mestorino, N. and Errecalde, J.O., 1997. Some pharmacokinetic parameters of oxfendazole in sheep. Veterinary Research Communications, 21 (4), 283-287

THE EFFECTS OF THE METHOD OF CALCULATION ON THE EVALUATION OF THE PHARMACOKINETIC PARAMETERS OF OXYTETRACYCLINE AFTER INTRAVENOUS ADMINISTRATION TO CALVES

Errecalde, J.O., Mestorino, N. and Mariño, E.L., 1997. The effects of the method of calculation on the evaluation of the pharmacokinetic parameters of oxytetracycline after intravenous administration to calves. Veterinary Research Communications, 21 (4), 273-281The aim of this study was to assess the differences in the values of the pharmacokinetic parameters attributable to the use of either linear or nonlinear regression analysis and to find the effect of weighting schemes on these differences. Six calves received 20 mg/kg oxytetracycline i.v. Blood samples were drawn during 72 h. The assay of the drug was performed microbiologically. A bicompartmental pharmacokinetic model was used, kinetic analysis being carried out by linear regression (LR) and by weighted least-squares nonlinear regression (WLSNLR). Statistical analysis included a test for normality, the Kruskall-Wallis test and ANOVA with log transformation.The A0, α and B0 did not show any statistically significant differences attributable to the mathematical method used. On the other hand, the statistically significant differences in the β values found using the Kruskall-Wallis test and ANOVA with log transformation could be attributed to the different methods employed. ANOVA with log transformation determined statistically significant differences between the parameters obtained by linear analysis and those obtained by WLSNLR when the weighting (w) was 1. When weights were 1/x, 1/x2 or 1/√ x, no statistically significant differences were found. The optimal weighting scheme was w = 1/x2 because of a more homogeneous scatter and random distribution of residuals about the abcissa axis in a plot of weighted residuals in the ordinate versus time in the abcissa. It was concluded that the use of these different procedures can give major variations in the apparent value of β, the most important pharmacokinetic parameter. The correct selection of the weighting procedure is therefore fundamental in obtaining the best estimate of this pharmacokinetic parameter in WLSNLR.

A DISCRIMINATORY STUDY OF A PHARMACOKINETIC MODEL FOR INTRAMUSCULAR GENTAMICIN IN SHEEP

The resulting serum concentrations were measured in six ewes after intramuscular administration of 10 mg/kg of gentamicin. The model providing the best fit for the experimental data was determined both by linear regression analysis between the experimental and theoretical values and by means of the Minimum Akaike Information Criterion Estimation (MAICE) test.Linear regression analysis showed certain differences favouring the monocompartmental model although the advantage was not conclusive. The MAICE test, however, permitted a clear discrimination in favour of the same model. When linear regression analysis is not conclusive, the MAICE test represents a good alternative.