Microbiological screening test validation for detection of tylosin excretion in milk of cows with low and high somatic cell counts.

Antibiotic residues in milk above tolerance levels interfere with dairy product processing and pose potential health risks to consumers. Residue avoidance programmes include, among other components, the observance of withdrawal times indicated in label instructions. Persistence of antibiotics in milk following treatment is influenced by drug, dosage, route of administration, body weight and mammary gland health status. Compositional changes that take place during intramammary infection (IMI) can affect antibiotic excretion in milk, thus modifying milk withdrawal time. The objectives of this study were to validate sensitivity and specificity of a qualitative microbiological method (Charm AIM-96) to detect tylosin in bovine composite milk and to determine the influence of subclinical IMI in tylosin excretion following intramuscular administration. For test validation, two groups of approximately 120 cows were used; one received a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg, while the other group remained as untreated control. Test sensitivity and specificity were 100% and 94.1% respectively. To determine the influence of subclinical IMI in tylosin excretion, two groups of seven cows, one with somatic cell counts (SCC) < or =250 000 cells/ml and the other with SCC > or =900 000, were administered a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg. Milk samples were obtained every 12 h for 10 days following treatment. Milk tylosin excretion averaged between 5 and 9 days for cows with low and high SCC respectively (P < 0.0001). Compositional changes in cows with high SCC most likely affect the pharmacokinetic characteristics of tylosin, extending the presence of the antibiotic in milk, thus influencing milk withdrawal times.

Daily rhythms in blood and milk lead toxicokinetics following intravenous administration of lead acetate to dairy cows in summer.

The objective of this study was to investigate circadian variations of blood and milk lead toxicokinetics in dairy cows in summer. Twenty lactating Holstein animals were randomly assigned to four treatments corresponding to different hours after onset of light (HALO): 2, 8, 14, and 20. Cows received a single intravenous administration of 2.5 mg/kg lead as lead acetate. Blood and milk samples were taken and analyzed by atomic absorption spectrophotometry. For each toxicokinetic parameter, a one-way analysis of variance (ANOVA) was performed to outline the existence of daily variations. Significant blood differences as a function of HALO were found for the hybrid constant of distribution (alpha), hybrid constant of elimination (beta), elimination half-life (t(1/2)beta), area under the curve (AUC), volume of distribution at steady state (V(ss)) and clearance (Cl(B)) (p<0.05). Half-life of elimination presented two peaks at 2 and 14 HALO. Milk data showed significant differences for maximum concentration and AUC (p<0.05). The ratio AUC(milk)/AUC(blood) was utilized to estimate penetration of lead in milk. It differed significantly throughout the day (p<0.05). Milk data for the significant parameters could be fitted to circadian rhythms. No circadian rhythms were detected in blood parameters or in the ratio AUC(milk)/AUC(blood).

Pharmacokinetics of sodium meclofenamate in pre-ruminant cattle

O perfil do meclofenamato sódico, uma droga antiinflamatória não-esteroidal, foi determinado em seis bezerros pré-ruminantes após administração intravenosa e intramuscular na dose de 2,2mg/kg de peso vivo. As concentrações de meclofenamato foram medidas empregando-se cromatografía líquida de alta performance. A farmacocinética do meclofenamato sódico, após as administrações intravenosa e intramuscular, caracterizou-se por rápida fase de distribuição (t½a ), 15,45±4,85min e 23,14± 7,24min para a administração intravenosa e intramuscular, respectivamente, seguida por longa fase de eliminação (t½b ), após a aplicação intramuscular (17,55±6,52h.). O volume aparente de distribuição (Vd) da administração intravenosa da droga foi moderado (0,72±0,12l/kg), e após um lapso da aplicação intramuscular, foi alta (3,51±1,05l/kg). Isso pode ser explicado pelo efeito flip-flop ou por evitar a via enteroépatica. A biodisponibilidade obtida após administração intramuscular foi de 61 por cento.

Some comparative aspects of the pharmacokinetics of tylosin in buffaloes and cattle.

The pharmacokinetics of tylosin were compared in cattle (Bos taurus) and buffaloes (Bubalus bubalis). Six animals received each a single dose of 10 mg/kg of tylosin tartrate by the intramuscular route. The serum concentration (Cmax) and the volume of distribution (Vd) presented significant differences between the two species. Cmax was 0.40 +/- 0.046 microg/ml for buffaloes and 0.64 +/- 0.068 microg/ml for cattle. Vd was 1.91 +/- 0.12 L/kg and 1.33 +/- 0.09 L/kg for buffaloes and cattle, respectively. However, as the present study did not show considerable differences in the pharmacokinetics of tylosin in buffaloes and cattle, similar dosage regimes of this drug can be recommended for both species.

Chronobiological variations of indomethacin pharmacokinetic parameters in sheep.

A two-phase study to investigate the influence of administration time on pharmacokinetics of indomethacin in sheep was performed. In phase I, 12 animals were allocated to four groups, each corresponding to a different time: 08:00, 14:00, 20:00, 02:00 h. Sheep received an intravenous administration of 1 mg/kg indomethacin. In phase II, each group was administered indomethacin with a 12-h difference compared to Phase I. The trial was performed in autumn, and animals were subjected to a natural light:dark cycle of 10:14 h. Blood samples were taken and processed by high performance liquid chromatography (HPLC) with ultraviolet detection. For each pharmacokinetic parameter, an analysis of variance was performed to outline the existence of chronobiological variations. Concentration at zero time (C0), hybrid constant for distribution and its half life, hybrid constant for elimination and its half-life, volume of distribution (V(d)), area under the curve (AUC(infinity)) and clearance rate (Cl), presented chronobiological variations (P < 0.05) and were fitted to a cosine equation. The following parameters adjusted to circadian rhythms: C(0) (acrophase: 13.9788 h); AUC(infinity) (acrophase: 13.4377 h); V(d) (acrophase: 0.8245 h) and Cl (acrophase: 1.4965 h). It was concluded that pharmacokinetic parameters of intravenously injected indomethacin in sheep would behave in a different, though predictable, manner according to the animal's biological clock.

Cadmium accumulation and distribution in slaughtered horse kidneys from the Argentine central region.

In this paper we report the results of surveys conducted in Argentina between 1997 and 1998 to know the Cd concentrations in kidney from horses of different age, sex, and origin. Cd in renal cortex and medulla was positively correlated, and higher concentrations in the cortex were found. No significant differences between values from left and right kidneys of the same animal were found. An increase in Cd levels with age of animals were observed, and no sex incidence was verified in renal Cd composition. No detectable residues were found in the fetuses tested. Levels observed in Argentine equines (n = 102) ranged from 4.3 to 83.8 microg Cd/g in kidney cortex, lower than those reported by other authors but higher than the action levels proposed by Argentine meat tissue species regulations. Therefore, the study remarks on the convenience of monitoring Cd in Argentine equines and gives relevant information for regulatory purposes to consider the limitation in the use of horse kidney as food for either human or animals.

Pharmacokinetics of miocamycin following intravenous administration to cattle.

The plasma pharmacokinetics for a single intravenous dose (10 mg/kg body weight) of miocamycin (a 16-membered macrolide drug) was investigated in Holando Argentino cattle (n = 5). Blood drug concentrations were determined by a microbiological method and data were best-fitted to a two-compartment open model. The pharmacokinetic profile consisted of a short distribution phase (t1/2 alpha = 7.41 +/- 0.53 min), followed by an extended terminal elimination phase (t1/2 beta = 2.49 +/- 0.23 h). The volume of distribution at steady-state was large (2.13 +/- 0.17 l/kg), suggesting extensive tissue distribution, the clearance value was 0.60 +/- 0.03 l/h.

Pharmacokinetics of indomethacin in sheep after intravenous and intramuscular administration.

The pharmacokinetics of indomethacin (1 mg/kg) was determined in six adult sheep after intravenous (i.v.) and intramuscular (i.m.) injection. Plasma concentrations were maintained within the therapeutic range (0.3-3.0 microg/mL) from 5 to 50 min after i.v. and from 5 to 60-90 min after i.m. administration. After two trials, indomethacin best fitted an open two-compartment model. The mean (+/- SD) volumes of distribution at steady state (Vd(ss)) were 4.10 +/- 1.40 and 4.21 +/- 1.93 L/kg and the mean clearance values (ClB) were 0.17 +/- 0.06 and 0.22 +/- 0.12 L/h x kg for i.v. and i.m. routes, respectively. The elimination phase half-lives did not show any significant difference between routes of injection (t1/2beta = 17.4 +/- 4.6 and 21.25 +/- 4.44 h, i.v. and i.m. respectively). After i.m. administration, plasma maximum concentration (Cmax = 1.10 +/- 0.68 microg/mL) was reached 10 min after dosing; the absorption phase was fast (Kab = 26 +/- 18 h(-1)) and short (t1/2ab = 2.33 +/- 1.51 min) and the mean bioavailability was 91.0 +/- 32.8%, although there was considerable interanimal variation. In some individuals, bioavailability was higher than 100%. This fact combined with the slower elimination phase after i.m. than after i.v. administration, could be related with enterohepatic recycling.

Chronopharmacokinetic behaviour of cyproterone acetate in rabbits.

Cyproterone acetate (CPA) is an antiandrogenic compound that shows a rhythmic toxicologic behaviour. The purpose of this study was to determine whether CPA pharmacokinetics in the rabbit were influenced by the administration time of day. Previously synchronised rabbits received a single intravenous dose of 4 mg kg(-1) of CPA at two hours after light onset (2 HALO) and 14 hours (14 HALO) after light onset. The drug concentration in plasma samples was determined by high performance liquid chromatography. The mean concentrations in plasma were significantly higher (P<0.05) in 2 HALO than in 14 HALO animals at five, 15 and 30 minutes after dosing. Both plasma concentration profiles were fitted to two-compartment open models. Mean A, Vc and Vss differed significantly between 2 and 14 HALO dosage (P<0.005). Temporal variations in plasma protein binding, drug distribution and in drug elimination may play an important role in explaining these results.

Influence of closure of the reticular groove on the bioavailability and disposition kinetics of meclofenamate in sheep.

Sodium meclofenamate is a non-steroidal anti-inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half-lives of the drug were 7.2 min and 542 min respectively, Vss was 1.68 L/kg and ClB was 2.47 mliter/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed (tmax-1 12-15 min, Cmax-1 3.30-24.01 micrograms/mliter; and tmax-2' 52.50-75 min, Cmax-2, 6.45-11.08 micrograms/mliter).

Comparison of the kinetics of sodium meclofenamate versus meclofenamic acid after oral administration to sheep.

Meclofenamates are non-steroidal anti-inflammatory agents used in ruminants for the prevention and the treatment of anaphylactic processes. The objective of the present work was to study possible kinetic variations due to the chemical form of meclofenamates administered by the oral route to adult sheep. Six Rubia del Molar female sheep (2-3 years old, 47-57 kg) were used. Initially, an intravenous administration of sodium meclofenamate (2.2 mg/kg bwt) was given; the obtained kinetic results were in agreement with data from other authors. Oral administrations (20 mg/kg bwt) of sodium meclofenamate and meclofenamic acid were then given. When the reticular groove was opened, both drug forms showed a single meclofenamate plasma peak; t2max were 60.0 +/- 10.61 min and 127.50 +/- 22.5 min for the sodium and acid form, respectively. The elimination rate constants (beta) were not significantly different, but the absorption half-lives were (14.69 +/- 3.21 min for the sodium form and 61.07 +/- 21.7 min for the acid form). The bioavailability was 48.6 +/- 4.3% for sodium meclofenamate and 65.1 +/- 2.8% for meclofenamic acid. Thus, the chemical form (sodium versus acid) alters the oral bioavailability and tmax of meclofenamates in adult sheep. These findings agree with the behaviour of meclofenamates in man.