Influence of a pig respiratory disease on the pharmacokinetic behaviour of amoxicillin after oral ad libitum administration in medicated feed.

The pharmacokinetic properties of amoxicillin in healthy and respiratory-diseased pigs were studied, after ad libitum administration of medicated feed. In addition, amoxicillin dose linearity and drug penetration into respiratory tract tissues were evaluated in diseased animals. The respiratory disease involves porcine reproductive and respiratory syndrome virus and bacterial agents such as Pasteurella multocida, Bordetella bronchiseptica and Streptococcus suis. Typical clinical signs and gross lesions of respiratory disease were observed. The plasma pharmacokinetic analysis was performed by means of a noncompartmental approach. After single intravenous bolus administration of amoxicillin to healthy pigs, the steady-state volume of distribution was 0.61 L/kg, the total plasma clearance was 0.83 L/h/kg and the mean residence time was 0.81 h. After oral bolus administration, the mean absorption time was 1.6 h and the peak plasma concentration (3.09 µg/mL) reached at 1.1 h postadministration. The oral bioavailability was 34%. For oral ad libitum administration, plasma concentration-time profiles were related to the feeding behaviour. Plasma concentrations at steady-state were established between 12 and 120 h. The pharmacokinetic parameters calculated (C(maxss) , C(minss) , C(avss) and AUC(24ss) ) showed significantly lower values in healthy pigs compared to diseased animals. This was in accordance with the significantly higher amoxicillin bioavailability (44.7% vs. 14.1%) and longer absorption period observed in diseased pigs. Amoxicillin dose linearity in diseased animals was established in a dose range of 4-18 mg/kg. On the other hand, tissue distribution ratio in diseased animals was 0.65 for bronchial mucosa, 0.48 for lung tissue and 0.38 for lymph nodes. Our results suggest that the pharmacokinetic properties and disposition of amoxicillin can be influenced by the disease state or by related factors such as changes in the gastrointestinal transit.

Effect of age and gender in the pharmacokinetics of albendazole and albendazole sulphoxide enantiomers in goats.

The kinetics of albendazole metabolites and albendazole sulphoxide enantiomers were studied in 2- and 14-month-old female and male goats, after a single oral dose administration (10mg/kg) of an albendazole formulation. Blood samples from the jugular vein were collected at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48 and 54h post-treatment and analyzed using a high performance liquid chromatography method. In all groups the area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of (+)-ABZSO were significantly higher than those of (-)-ABZSO. The AUC and C(max) values obtained for (+)-ABZSO and (-)-ABZSO in adult animals were higher compared to the results in young animals, showing significant differences except for (+)-ABZSO in female animals. In young animals, independently of gender, the C(max) appeared earlier compared to adult animals. The mean residence time (MRT) values were shorter in young animals compared to adult animals for all compounds analyzed. No sex-related differences were found for any of the parameters calculated except for the (+)-ABZSO from adult animals.

Transplacental transfer of propofol in pregnant ewes.

Propofol is an injectable anaesthetic that is currently used both in veterinary and human medicine for the induction and maintenance of anaesthesia. Although little is known about the pharmacokinetics of propofol in fetuses, it is widely used in obstetric procedures, particularly in caesarean section. This study determines the pharmacokinetics of propofol in pregnant ewes in the last third of pregnancy, and placental transfer and pharmacokinetics in fetuses after the administration of a 6 mg/kg intravenous (i.v.) bolus (phase 1) or a 6 mg/kg i.v. bolus followed by continued infusion of 0.4 mg/kg/min. In ewes, the area under the blood concentration-time curve (AUC) and C(max) (8.6 mgh/mL and 9.5mg/mL, respectively) was higher than those of the fetus (1.6 mgh/mL and 1.19 mg/mL, respectively). The mean half-life was 0.5h in the dam and 1.1h in the fetus.

Albendazole sulphoxide enantiomers in pregnant rats' embryo concentrations and developmental toxicity.

Three single oral doses (8.5, 10, and 14 mg/kg) of a racemic formulation of albendazole sulphoxide (ABZSO) were administered to pregnant rats on day 10 of gestation. Mother plasma and embryo concentrations of ABZSO enantiomers and albendazole sulphone (ABZSO(2)) were determined 9 h after administration. The (-)-ABZSO enantiomer showed higher peak concentrations in both maternal plasma and embryo than the (+) enantiomer. An increase in embryo concentrations of ABZSO enantiomers and ABZSO(2) was only observed when dose rose to 14 mg/kg. There was an increase in resorption when the dose increased, but significant differences were only found in the higher dose group when compared with the other groups. The incidence of external and skeletal malformations (mostly of the tail, vertebrae and ribs) rose significantly in the 10 mg/kg group, producing almost 20% and 90% of malformed fetuses, respectively, and gross external and skeletal abnormalities in the thoracic region and limbs were also found.

Placental transfer of albendazole sulphoxide enantiomers in sheep.

Albendazole sulphoxide (ABZSO) is an anthelmintic drug used in veterinary practice. Its molecule has a chiral centre in the sulphur atom and racemic formulations are always used. The kinetics of the ABZSO enantiomers in the last third of pregnancy in ewes, and the placental transfer to the fetus, were studied after a single-dose oral administration (7.5 mg/kg) of a racemic formulation. In mothers, the area under the plasma concentration-time curve (AUC) and C(max) values of (+)-ABZSO (42.4+/-10.5 microg/mL and 1.9+/-0.4 microg/mL, respectively) were higher than those of (-)-ABZSO (15.3+/-5.1 microg/mL and 1.0+/-0.3 microg/mL). The MRT values were 17.0+/-1.6 h for (+)-ABZSO and 13.1+/-1.8 h for (-)-ABZSO. Similar kinetic parameters were obtained in the fetus for both enantiomers, but the fetal concentrations were lower compared with values for the dam. The AUC ratio between (-)-ABZSO/(+)-ABZSO in the dam was 0.36 and in the fetuses 0.64, indicating a higher impairment for the (+)-enantiomer in its placental transfer to the fetus.

Allometric analysis of thiamphenicol disposition among seven mammalian species.

The pharmacokinetics of thiamphenicol (TAP), a broad-spectrum antibiotic, was determined in male mice, rats, rabbits, dogs, pigs, sheep and calves. The relationship between the main pharmacokinetic parameters of TAP and body weight (W) was studied across these seven mammalian species, using double-logarithmic plots. The experimental values of volume of distribution (Vss), clearance (Cl) and elimination half-life (t(1/2)beta) were plotted, and extrapolated values were determined from corresponding allometric equations. These parameters were fitted to the following equations: Vss=0.98W0.92, Cl=15.80W0.76 and t(1/2)beta=0.94W0.20, and present good correlation (Vss: r2=0.997, P < 0.001; Cl: r2=0.976, P < 0.001, t(1/2)beta: r2=0.852, P < 0.005), that is expected of a drug eliminated primarily by renal glomerular filtration, with insignificant hepatic metabolism. For the t(1/2)beta, the extrapolated and observed values were similar. The extrapolated values of Cl were close to the experimental values, except for the mouse and pig mean percent error [(M.E.) equal to 62 and 119%, respectively], while the extrapolated and observed values for the Vss were very similar. The comparison between experimental and extrapolated values suggests that it could be possible to extrapolate, with good prediction, the kinetic parameters of this drug for mammalian species, using allometric scaling, except for the species that eliminate the drug by a combination of renal excretion and hepatic metabolism.

Effect of ruminal microflora on the biotransformation of netobimin, albendazole, albendazole sulfoxide, and albendazole sulfoxide enantiomers in an artificial rumen.

The effect of ruminal flora on the disposition of benzimidazole anthelmintic drugs was studied in dual-flow continuous-culture fermenters (artificial rumens). Six 1,320-mL artificial rumens were inoculated with ruminal fluid and fermentation conditions were maintained constant at 39 degrees C, pH 6.4, solid dilution rate of 5%/h, and liquid dilution rate of 10%/h to simulate standard ruminal fermentation conditions. The study was repeated in two consecutive periods. Two hours after the inoculation of rumen fluid, the fermenters were fed 30 g of a 60:40 forage:concentrate ration. Within each period two fermenters per treatment were immediately dosed with 104 mg of netobimin, 52 mg of albendazole, or 39 mg of albendazole sulfoxide. Concentrations of netobimin, albendazole, albendazole sulfoxide and its enantiomers, and albendazole sulfone were analyzed by high performance liquid chromatography at 0.25, 0.5, 1, 2, 4, 6, and 8 h after dosage. Reductive metabolism by the ruminal bacteria was observed, favoring the production of albendazole, the most potent anthelmintic molecule. No differences in the production or consumption of albendazole sulfoxide enantiomers were observed, indicating that the ruminal bacteria metabolism was not enantioselective. Because benzimidazole anthelmintic drugs are generally administered orally, the ruminal flora play an important role in the bioavailability of these drugs. In our study, increased concentrations of albendazole in the three treatments, due to reductive ruminal biotransformation, suggests that ruminal biotransformation may improve the efficacy of orally administered netobimin, albendazole, and albendazole sulfoxide.

Pharmacokinetic behaviour of albendazole sulphoxide enantiomers in male and female sheep.

Benzimidazole anthelmintic drugs are widely used in veterinary practice. Albendazole sulphoxide (ABZSO) is a benzimidazole drug with two enantiomers, as a consequence of a chiral centre in the sulphoxide group. The kinetics of these enantiomers were studied in male and female sheep. Plasma samples were obtained from the animals between 0.5 and 72 h after oral administration of 7.5 mg/kg of a racemic formulation of ABZSO (total-ABZSO). After a liquid-liquid extraction, the samples were analysed by HPLC to determine the concentrations of total-ABZSO and of the sulphone metabolite (ABZSO2). During the chromatographic analysis, the ABZSO peak was collected and reanalysed by an HPLC technique using a Chiral AGP column to quantify the enantiomeric proportion therein. After kinetic analysis, the AUCs obtained for the (+)-ABZSO were 5.8 and 4.0 times higher than those for the (-)-ABZSO in male and female animals, respectively. The mean residence times were 23.4 and 16.1 h for (+)-ABZSO and 22.2 and 17.4 h for (-)-ABZSO for male and female animals, respectively. The only significant difference between the sexes (p < 0.05) was in the Tmax of the (-)-ABZSO. Comparing both enantiomers within each sex, significant differences were found in all the kinetic parameters. Finally, no kinetic differences were found between sex for total-ABZSO or ABZSO2.

Liquid chromatographic determination of fenbendazole residues in pig tissues after treatment with medicated feed.

Fenbendazole (FBZ) is an anthelmintic widely used in farm animals to treat parasitic infestations. In pigs, it is administered in the food. The aim of this study was to validate an analytical method for the determination of FBZ and its metabolites in pig tissues. This method is based on oxidation of FBZ and its sulfoxide metabolite to the sulfone metabolite (FBZSO2). The limit of quantitation for this method is 20 ng FBZSO2/g for all tissues. The maximum residue limits (MRLs) established for FBZ and its metabolites in pig tissues are 50 ng/g for muscle, fat, and kidney and 500 ng/g for liver. This method is based on a liquid-liquid extraction followed by an oxidation with peracetic acid and a cleanup procedure based on 2 liquid-liquid extractions. Determination is achieved by high-performance liquid chromatography with ultraviolet detection. The present method is adjusted to the MRL established for FBZ and its metabolite residues. The analysis of the residues shows that after 72 h posttreatment, no FBZSO2 was detected in muscle, fat, and kidney and that liver levels were below the MRL.