Clinical pharmacokinetic characterization of norfloxacin nicotinate in swine following systemic administration.

Norfloxacin nicotinate (NFN) is a new water-soluble fluoroquinolone antibacterial agent. The in vitro activity of NFN for microorganisms isolated from swine and the pharmacokinetic properties of NFN following single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration were investigated. The minimal inhibitory concentrations (MIC's) of NFN for a wide range of reference (ATCC-American Type Culture Collection) microbial swine isolates, comprising 21 bacterial and 5 mycoplasmal species, ranged between 0.03 micrograms/ml (for Salmonella cholerasuis and Actinobacillus pleuropneumonia) and 12.5 micrograms/ml (for Streptococcus porcinus). The MIC of NFN for Mycoplasma hyopneumoniae, the causative agent of enzootic pneumonia of pigs, was < 1.0 microgram/ml although M. hyosynoviae was less sensitive, with a MIC value of 3.12 micrograms/ml. The MIC values of the drug for swine field isolates, comprising 8 bacterial species, were in good agreement with the values determined for the corresponding ATCC strains. Pharmacokinetic values for NFN were calculated following i. v. administration at 7.0 mg/kg and i. m. and s. c. administration at 14.0 mg/kg in a 3-way cross over study involving 6 pigs. Plasma concentrations of unchanged drug were determined by HPLC during 24 h post injection. Plasma NFN concentrations measured after i.v. dosing best fitted a 2-compartment open system pharmacokinetic model. The harmonic mean distribution half-life (t1/2 alpha) and elimination half-life (t1/2 beta) were 4.2 minutes and 2.1 h, respectively. The mean residence time (MRT) was 2.9 +/- 0.6 h and the steady state volume of distribution (Vss) was 3.2 +/- 0.1 l/kg. The mean t1/2 beta values after either i. m. or s. c. administration were 4.45 h with very rapid absorption rates (< 15 min to peak plasma drug concentration). Bioavailability was 51-64%. Less than 20% and 25% of the dose were excreted in the urine as parent drug during the first 24 h after i.v. and s.c. dosing, respectively whereas the amount of unchanged drug recovered in the feces was very small (1.3 to 1.6% of the dose). The pharmacokinetic and MIC data generated in the course of the present study suggest that a dose schedule of 14.0 mg/kg injected i. m. or s. c. every 24 h is capable of achieving and maintaining tissue drug concentrations of potential therapeutic value for the treatment of the most common bacterial and mycoplasmal infections in swine.