The biopharmaceutics and oral bioavailability of two forms of oxytetracycline to the white shrimp, Litopenaeus setiferus☆

Abstract The pharmacokinetics of the antibiotic, oxytetracycline (OTC), were examined following oral dosing in the white shrimp, Litopenaeus setiferus . These studies were conducted to improve dosing efficacy and safety for OTC use in treating shrimp. Oxytetracycline is available commercially for feed preparation as a premix of two different forms of the parent drug, the dihydrate form (OXTC) and the monoalkyl (C8-18) trimethyl quaternary salt form (TMF). Both pharmacokinetics and physicochemical properties were studied under conditions simulating a marine environment. Physicochemical properties studied were solubility and short-term stability of the premixes and dissolution following incorporation of the premix into feed. The oral bioavailability of OTC from feed containing either form of OTC was evaluated and compared in shrimp following single and multiple dosing. Hemolymph levels of OTC at predetermined time intervals after dosing were measured by High Performance Liquid Chromatography (HPLC). The hemolymph OTC levels were fitted to appropriate pharmacokinetic models to determine parameters as is typically done in pharmacokinetic evaluations. OTC was more than twice as soluble from OXTC than from the TMF premix. After being pelleted with feed, dissolution studies showed nearly identical release profiles for the two OTC forms. It appears that the medicated feed acts like a matrix resulting in a controlled release dosage form for OTC with 100% release requiring about 24 h. The short-term stability study indicated that OTC from the TMF premix was more stable than OXTC in seawater under ambient conditions. While this might improve bioavailability and therapeutic efficacy, it will lengthen its residence time in the environment if released with consequent increased environmental risk. Hemolymph OTC concentration versus time profiles following single dose oral administration were well described by a triexponential equation suggesting a two compartment pharmacokinetic model. OTC was well absorbed from both salt forms when orally administered; bioavailability was better than reported in the literature for finfish. To evaluate bioequivalency, the rate and extent of absorption were compared for the two forms of OTC. The maximum hemolymph concentration ( C max ) and time to achieve the maximum ( t max ) were not significantly different for the two forms, but the apparent bioavailability ( F ) and area under the concentration–time curve (AUC) was found to be statistically greater for the OXTC form. In both cases, peak concentrations were delayed, suggesting a unique mechanism for absorption in shrimp. While single dose studies with individual shrimp suggested that OXTC was the preferred form of OTC, multiple dose studies with multiple shrimp showed that practically there is little difference in therapeutic efficacy or depuration times between the two forms of OTC. Overall, either form of OTC can be useful for the aquaculturing of shrimp; it appears that OTC can be used safely in a product for human consumption following a reasonably short withdrawal period.