Pharmacokinetics and bioavailability of doxycycline hyclate after oral administration in calves.

The bioavailability and pharmacokinetics of doxycycline hyclate were determined in calves with immature rumen function. The bioavailability of doxycycline after oral administration in a milk replacer was approximately 70%. The elimination half-life of doxycycline was found to be 9.5 +/- 3.0 h. after intravenous administration, and 12.6 +/- 5.0 h. after single oral administration. Plasma concentrations were determined after repeated oral administration of doxycycline dissolved in a milk replacer, at a dose of 5 mg per kg body weight, twice daily. During the period of administration, the plasma concentrations varied between Cmin of 1.0 +/- 0.19 mg/L and Cmax of 2.3 +/- 0.19 mg/L.

Oral absorption and bioavailability of flumequine in veal calves.

The oral absorption and bioavailability of flumequine was studied in 1-, 5- and 18-week-old calves following intravenous and oral administration of different formulations of flumequine (Flumix, Flumix C and pure flumequine). Increasing age had a negative influence on the Cmax after the administration of Flumix, based on a larger VD in the older calves. The Cmax decreased from 5.02 +/- 1.46 micrograms/ml in the first week to 3.28 +/- 0.42 micrograms/ml in the 18th week. Adding colistin sulfate to the flumequine formulation and administring pure flumequine mixed with milk replacer had a negative effect on the Cmax of flumequine after oral administration of 5 and 10 mg/kg body weight. The bioavailability of the orally administered flumequine formulations was 100% in all cases except after the administration of Flumix C, for which it was 75.9 +/- 18.2%. The urinary recovery of flumequine after intravenous injection of a 10% solution varied from 35.2 +/- 2.3% for Group B, to 41.2 +/- 6.3% for Group C. The dosage of 5 mg/kg body weight Flumix twice daily in 1-week-old veal calves is sufficient to reach therapeutic plasma concentrations, based on a MIC value of 0.8 micrograms/ml of the target bacteria. In older calves it is advisable to increase the dosage 7.5 or 10 mg/kg body weight every 12 hours. In combination with colistin sulfate it is also advisable to increase the dosage slightly because of the negative effect of the colistin sulfate on the Cmax of flumequine.

Three phase elimination of oxytetracycline in veal calves; the presence of an extended terminal elimination phase.

The pharmacokinetics of oxytetracycline were studied after both intravenous (i.v.) and intramuscular (i.m.) administration to a group of five veal calves. Blood samples were taken frequently during the terminal elimination phase in order to calculate a reliable elimination rate constant. Because of the low limit of quantification of the method of analysis used, oxytetracycline plasma concentrations could be monitored over a 12-day period of time. After the intravenous administration of oxytetracycline, data were fitted according a three-compartment model. After i.m. administration, plasma-concentration-time curves could best be described by a two-compartment model. It was demonstrated that a very slow terminal elimination phase was present both after i.v. and i.m. administration with a half-life of approximately 95 h. The data show that this phase cannot be explained by slow absorption from the injection site and that release of oxytetracycline incorporated into bone is not a likely explanation.

Correlation between tissue and plasma concentrations of oxytetracycline in veal calves.

Mercer et al. (1977) proposed a three-phase experimental design to establish withdrawal times, based on plasma pharmacokinetics. This approach was the premise of a study in which plasma pharmacokinetics and tissue depletion data of oxytetracycline after intramuscular administration were correlated. Correlations between estimated and measured concentrations were shown to be significant for kidney tissue (r = .9236, p < .001), liver tissue (r = .9302, p < .01) as well as for muscle tissue (r = .9045, p < .001). The data presented support the pharmacokinetic approach as proposed by Mercer et al. (1977) and demonstrate that tissue elimination rates correlate highly with elimination rates in plasma. Although generalizations must be applied with caution, this article shows that when certain criteria are fulfilled, plasma pharmacokinetics can reliably predict tissue withdrawal times.

Pharmacokinetics, metabolism and renal clearance of flumequine in veal calves.

The pharmacokinetics of flumequine was studied in 1-, 5- and 18-week-old veal calves. A two-compartment model was used to fit the plasma concentration-time curve of flumequine after the intravenous injection of 10 mg/kg of a 10% solution. The elimination half-life (t1/2 beta) of the drug ranged from 6 to 7 h. The Vd beta and ClB of 1-week-old calves (1.07 l/kg, 1.78 ml/min/kg) were significantly lower than those of 5-week-old (1.89 l/kg, 3.23 ml/min/kg) and 18-week-old calves (1.57 l/kg, 3.10 ml/min/kg). After the oral administration of 10 mg/kg of a 2% flumequine formulation mixed with milk replacer, the Cmax was highest in 1-week-old (9.27 micrograms/ml) and lowest in 18-week-old calves (4.47 micrograms/ml). The absorption was rapid (Tmax of approximately 3 h) and complete. When flumequine itself and a formulation containing 2% flumequine and 20 X 10(6) iu of colistin sulphate were mixed with milk replacer and administered at the same dose rate, absorption was incomplete and Cmax was lower. The main urinary metabolite of flumequine was the glucuronide conjugate (approximately 40% recovery within 48 h of intravenous injection) and the second most important metabolite was 7-hydroxy-flumequine (approximately 3% recovery within 12 h of intravenous injection). Only 3.2-6.5% was excreted in the urine unchanged. After oral administration a 'first-pass' effect was observed, with a significant increase in the excretion of conjugated drug. For 1-week-old calves it is recommended that the 2% formulation should be administered at a dose rate of 8 mg/kg every 24 h or 4 mg/kg every 12 h; for calves over 6 weeks old, the dose should be increased to 15 mg/kg every 24 h or 7.5 mg/kg every 12 h. The formulation containing colistin sulphate should be administered to 1-week-old calves at a flumequine dose of 12 mg/kg every 24 h or 6 mg/kg every 12 h.

Bioavailability of flumequine after semisimultaneous administration to veal calves.

The absolute bioavailability of flumequine after semisimultaneous intramuscular administration as a water-based suspension to veal calves was 92 +/- 14%. The semisimultaneous experimental design provided a reliable determination of absorption rate and demonstrated flip-flop pharmacokinetics. No period or sequence effects were detected. Calculated elimination rate, clearance, and volume of distribution after intravenous administration were comparable to values obtained from traditional design studies. The semisimultaneous experimental design proved to be valuable for the assessment of bioavailability and pharmacokinetics of drugs in food-producing animals while preventing violation of basic clearance assumptions.