Comparative pharmacokinetics and bioavailability of eight parenteral oxytetracycline‐10% formulations in dairy cows

Abstract

SU MM A R Y In plasma and milk the oxytetracycline (OTC) concentrations were determined following a single intramuscular administration of eight 10%-formulations to dairy cows at a dose of approximately 5 mg/kg. Two of these formulations were injected intravenously to obtain reference values of the drug's pharmacokinetic parameters. The eight formulations were compared and evaluated pharmacokinetically with respect to absorption rate, peak plasma and milk OTC concentrations, biological half-life, and relative bioavailability. The mean maximum plasma OTC concentrations, ranging from 2.0 to 4. 1 pg/ml, were achieved between 4 and 12 hours post injection, depending on the formulation involved. The mean maximum milk OTC concentrations, in the range between 0.92 and 1.43 mg/ml, were achieved 12 to 24 h p. i. The OTC milk concentration-time profile ran parallel to the OTC plasma concentration-time profile. After intravenous administration the time for the appearance of OTC in milk was shorter (1-2 hours p.i.), the peak milk OTC concentration was higher (1.7-1.9 pg/ml) and achieved earlier (6-8 h p.i.). and the OTC persistence in milk shorter than after i.m. administration. Formulations exhibiting the lowest clinically noticeable irritation showed the most favourable pharmacokinetic characteristics: rapid absorption with the highest peak plasma OTC concentrations and good bioavailability. The plasma and milk protein binding for OTC was respectively 71.7± 7.4% and 84.8 ± 5.45%. Withdrawal times for milk and edible tissues are presented on the basis of preset tolerance or detection limits.

Comparative pharmacokinetics, bioavailability and renal clearance of five parenteral oxytetracycline‐20% formulations in dairy cows

“…administration of OTC the OTC appearance time in milk, the peak milk OTC concentration, and relative persistence are shorter than after the i.m. dosage, which confirms earlier investigations (14). After i.m.…”

“…The pharmacokinetic parameters derived from the i.v. data of product F, presented in Table 2, were similar to those reported previously (13,14). The final elimination half-life (T1127) was 9.5 ± 2.1 h., the distribution volume (VDarea) 1.02 ± 0.16 litre/kg, and the total body clearance (C1B) 0.076 litre/kg/hr.…”

“…The differences observed may presumably be due to various concentration and types of PVP, other organic solvents incorporated, and additives, which were not disclosed completely by the manufacturers. Despite the low injection volume in each injection site (15 ml), formulations containing mainly glycerolformal (product D) and mainly aqueous 2-pyrrolidone (product A) both gave severe irritation, which has also been reported previously for other injection volumes, dose levels, and species (6,12,14,16,21,22 Product A showed a very fast initial absorption but after approximately one hour the absorption slowed down abruptly. This phenomenon had been noted previously by Toutain et al (19), who assumed an immediate availability of a fraction of the dose, the remainder being absorbed more slowly.…”

“…The degree of irritation depends, among other things on the OTC concentration in the formulation, the irritation caused by the solvent system itself, the extent of spread between the muscles (absorption surface), absorption rate of OTC and the solvent, the amount or concentration of drug precipitated at the injection site after absorption of the solvent, and the injection volume (12,14,15,16,22).…”

“…Analysing of the intramuscular OTC plasma data of each animal revealed the Cmax, the Tmax, the absorption rate T 1/2abs., the concentration-time intercept (Co), the area under the curve (AUC), and the half-life of OTC (T1/2) (2,8). The relative bioavailability (%) and the withdrawal time for milk, organs, and muscle were calculated on the basis of the plasma concentration data beyond 48 h p.i., using tissue plasma concentration ratios assumed to be time-independent (muscle and milk to plasma OTC concentration ratio = 1; kidney to plasma OTC concentration ratio = 10) (14,15). Standard procedures were performed for calculating the renal clearance of oxytetracycline and creatinine and for statistical analysis (two-tailed Student's t-test, regression analysis, mean and standard deviation calculations).…”