Abstract
The pharmacokinetic–pharmacodynamic predictor of antimicrobial activity for tetracyclines is reported to be the area under the concentration–time curve at steady state (AUCss) divided by the minimal inhibitory concentration of the targeted pathogen. Here, we estimate AUCss values for oxytetracycline (OTC) in serum of rainbow trout Oncorhynchus mykiss by using a destructive sampling study design. Seventy-two rainbow trout were fed OTC-medicated feed at 74.7 ± 1.5 mg/kg (mean ± SD) body weight (BW) by oral gavage for 10 consecutive days. Serum was collected from nine fish at 1, 3, 6, 8, 10, 12, 15, and 22 d after dosing began. Serum OTC concentrations were measured by high-performance liquid chromatography with a 0.01-μg/mL limit of detection. The average OTC AUCss was 29.2 μg × h/mL and was estimated using nonlinear mixed-effects modeling and bootstrap resampling techniques. The elimination half-life was estimated as 85.0 h, and the fraction of steady state achieved was estimated as 0.85. The calculated AUCss (24.8 μg × h/mL) following 10 d of oral dosing with 75 mg OTC/kg BW was less than the estimated AUCss. Results suggest that the pharmacokinetics of OTC exposure, including the AUCss, is better evaluated by using multiday dosimetry than by using a standard single-dose protocol.
Received September 29, 2011; accepted January 30, 2012
ACKNOWLEDGMENTS
This work was supported in part by the Oak Ridge Associated Universities through a grant sponsored by the FDA. We would like to thank Christie Decker, Mark McDonald, and Sam Howard for maintaining the animals used in this work. Reference to trade names does not imply endorsement by the U.S. Government.