Plasma and urine disposition and dose proportionality of ceftiofur and metabolites in dogs after subcutaneous administration of ceftiofur sodium.

Nine male dogs (10.3-13.5 kg body weight) were randomly assigned to three groups of three dogs each and administered ceftiofur sodium subcutaneously as a single dose of 0.22, 2.2, or 4.4 mg ceftiofur free acid equivalents/kg body weight. Plasma and urine samples were collected serially for 72 h and assayed for ceftiofur and metabolites (derivatized to desfuroylceftiofur acetamide) using high-performance liquid chromatography. Urine concentrations remained above the MIC90 for Escherichia coli (4.0 micrograms/mL) and Proteus mirabilis (1.0 micrograms/mL) for over 24 h after doses of 2.2 mg/kg (8.1 micrograms/mL) and 4.4 mg/kg (29.6 micrograms/mL), the interval between treatments for ceftiofur sodium in dogs, whereas urine concentrations 24 h after dosing at 0.22 mg/kg (0.1 mg/Ib) were below the MIC90 for E. coli and P. mirabilis (0.6 microgram/mL). Plasma concentrations were dose-proportional, with peak concentrations of 1.66 +/- 0.0990 micrograms/mL, 8.91 +/- 6.42 micrograms/mL, and 26.7 +/- 1.07 micrograms/mL after doses of 0.22, 2.2, and 4.4 mg/kg, respectively. The area under the plasma concentration versus time curve, when normalized to dose, was similar across all dosage groups.

Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment.

Ceftiofur sodium, a broad spectrum cephalosporin antibiotic approved for veterinary use, is metabolized to desfuroylceftiofur which is conjugated to micro as well as macromolecules. Twelve horses, weighting 442-618 kg, were injected intramuscularly with a single dose of 2.2 mg ceftiofur/kg (1.0 mg/lb) body weight. Blood was collected at various intervals over 24 h after treatment. Three groups of four horses each were euthanized and lungs were collected at 1, 12, and 24 h after treatment. The concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the plasma and lungs was determined by converting them to desfuroylceftiofur acetamide (DCA) and measured DCA by high performance liquid chromatography with UV detection. The average maximum concentration (Cmax) of desfuroylceftiofur and related metabolites in plasma expressed as ceftiofur equivalents was 4.46 +/- 0.93 micrograms/ml occurred at 1.25 +/- 0.46 h after treatment. These concentrations declined to 0.99 +/- 0.16, 0.47 +/- 0.15 and 0.17 +/- 0.02 microgram/ml at 8, 12, and 24 h, respectively. The mean residence time of ceftiofur metabolites was 6.10 +/- 1.27 h. Concentrations of desfuroylceftiofur and desfuroylceftiofur conjugates in the lungs of horses expressed as ceftiofur equivalents were 1.40 +/- 0.36, 0.27 +/- 0.07, and 0.15 +/- 0.08 micrograms/ml at 1, 12, and 24 h, respectively. These concentrations of the drug at 12 and 24 h in lung homogenate were similar but slightly lower than plasma concentrations in the same horses, and the plasma pharmacokinetic values including half-life were similar to those observed at the approved dose of 1.1-2.2 mg ceftiofur/kg body weight administered intramuscularly once daily for 3-5 days in cattle.

Depletion of intramuscularly injected ceftiofur from the milk of dairy cattle.

Ceftiofur sodium, a new broad-spectrum cephalosporin, has been approved in the US, Canada, and several other countries throughout the world to treat bovine respiratory disease in cattle and dairy cows. In Experiment 1, 6 lactating cows were intramuscularly treated with 2.29 mg of [14C]ceftiofur/kg of BW daily for 5 d. In Experiment 2, 30 additional cows at three locations were similarly treated with 2.2 mg of ceftiofur (unlabeled)/kg of BW. Milk was collected every 12 and 24 h after each dose and every 12 h up to 5 d after the last dose. The majority of milk samples, both during treatment (12 and 24 h after each dose) and after the last dose (up to 5 d following ceftiofur treatment), were negative by screening procedures based on microbial inhibition (Delvotest-P, Bacillus stearothermophilus disk assay, and cylinder plate assays). The receptor-binding Charm Test II assay, which has a limit of detection of .005 ppm of ceftiofur, gave positive tests for milk samples up to 48 h following treatment. When the Charm Test II assay is used with .008 IU/ml of penicillin as a positive control, 44% of the samples from individual cows were negative at 12 h posttreatment. Ninety percent of the samples from individual cows were negative at 24 h after the last treatment. The use of ceftiofur in dairy cattle in accordance with the label directions does not result in total residues in milk higher than the FDA-calculated safe concentration of 1-ppm ceftiofur equivalents. The milk from individual cows did not test positive by the commercial screening assays examined in this study, except for the Charm Test II. The Charm Test II was 90% negative using the Charm Sciences criteria at 24 h after the last treatment.

Liquid chromatographic determination of desfuroylceftiofur metabolite of ceftiofur as residue in cattle plasma.

A liquid chromatographic (LC) method has been developed for the determination of the desfuroylceftiofur metabolite of ceftiofur as a residue in the plasma of animals. Plasma sample in 0.1M pH 8.7 phosphate buffer containing dithioerythritol is incubated under nitrogen for 15 min at 50 degrees C. The sample is centrifuged, charged to a C18 cartridge, and washed with 0.1M ammonium acetate. The desfuroylceftiofur residue on the cartridge is derivatized by adding 0.1M ammonium acetate containing iodoacetamide and letting the cartridge stand in the dark for 30 min. The cartridge is then drained and rinsed, and the desfuroylceftiofur acetamide is eluted with methanol. The mixture is evaporated to dryness, dissolved in pH 10.6 sodium hydroxide, and charged to a SAX cartridge. The derivative is eluted with 2% acetic acid, reduced in volume, and dissolved in mobile phase for liquid chromatography. The LC system includes a C8 column and guard cartridge with UV detection at 254 nm. The gradient mobile phase (flow rate 1 mL/min) is 0.01M pH 5 ammonium acetate programmed to 29% methanol-water (60 + 40) in 25 min. Recoveries were 90-100% with a sensitivity of 0.1 ppm or less. The procedure has been applied to the plasma of cattle, rats, horses, pigs, and dogs.

The effects of an oral contraceptive on plasma growth hormone and glucose tolerance in two strains of rats.

Effects of an oral contraceptive on plasma growth hormone and glucose tolerance were studied in two strains of rats, Sprague-Dawley, a normal strain, and BHE, a carbohydrate-sensitive strain. Ethynyl estradiol and norgestrel, combined in a dose representative of the clinical preparation of Ovral were given for 21 days. Plasma growth hormone was measured following sodium pentobarbital stimulation. In both strains fasting blood glucose levels were unchanged following oral contraceptive therapy, however, a strain difference in response to a glucose load was found. With contraceptive steroid treatment, Sprague-Dawley rats developed an impaired tolerance to glucose during the latter part of the glucose tolerance test. BHE control animals had an abnormal response to a glucose load which improved with oral contraceptive therapy. No significant correlation between growth hormone changes and changes in glucose tolerance during contraceptive steroid treatment were observed. Both strains of rats receiving oral contraceptives gained less weight than their controls, however, the difference was statistically significant only in the Sprague-Dawley strain.

PIP: The effects of Ovral (norgestrel plus ethinyl estradiol) on plasma growth hormone (GH) levels and glucose tolerance were investigated in Sprague-Dawley and a carbohydrate-sensitive strain (BHE) of rats. Sodium pentobarbitol was used to stimulate GH production. Fasting blood glucose levels were not altered by treatment with Ovral in either strain. However, under a glucose load, Sprague-Dawley rats developed an impaired tolerance during the latter part of the glucose tolerance test, while treatment with the oral contraceptive improved an impaired response to glucose load in BHE animals. A good correlation between changes in GH and glucose tolerance during treatment could not be established. Sprague-Dawley rats had a significant (p less than .01) decrease in the rate of body weight increase compared with controls.