Temperature-dependent non-linear pharmacokinetics of florfenicol in Nile tilapia (Oreochromis niloticus) and its implementation in optimal dosing regimen determination

While the majority of drugs used clinically at therapeutic range usually follow dose-independent or linear pharmacokinetics (PK); as the administered dose is increased the PK behavior may become dose-dependent or non-linear without recognition and may lead to adverse effects. The current study aimed to investigate the extent of non-linear PK of florfenicol (FF) in Nile tilapia, and for the first time, to investigate the effect of temperature on non-linear PK behavior. For each temperature level (24, 28, and 32 degrees C), the fish were orally administered with FF at a single dose of 10, 15, 30 and 45 mg/kg. The serum concentrations of FF were analyzed by HPLC-UV and the PK parameters were determined by 2-compartmental model. Regardless of the rearing temperature level, increasing the FF doses from 10 to 45 mg/kg resulted in about 1.3-1.5 fold increases in the dose-normalized area under the serum concentration-time curve (AUC/dose), longer elimination half-life (t(1/2 beta)), and slower clearance (CL/F). The dose-dependency of the above parameters but not absorption half-life (t(1/2Ka)) and volume of distribution (Vd) suggested that the FF non-linearity was most likely due to saturation of metabolism. For the first time, the effect of temperature on non-linearity was revealed and discovered that the non-linearity happened at lower dose in the warmer temperature (>= 30 mg/kg at 28 and 32 degrees C) than in the cooler temperature (>= 45 mg/kg at 24 degrees C), which correlated well with the lower Michaelis-Menten constant (K-m) at the warmer temperature. In the presence of non-linear PK, a modified Michaelis-Menten equation could be successfully applied to determine an optimal dosing regimen. The accuracy of the calculated dosage was verified by the oral multiple-dose study. Medication of Nile tilapia with a high dose of FF should be done with great caution especially at the warmer water as higher dosage may be required and that non-linearity may happen at lower dose such that it would cause a higher risks of drug toxicity and tissue residue violation.