| This dissertation describes several aspects of cefixime's pharmacokinetics in dogs.;The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound.;To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 (+OR-) 17% (mean (+OR-) SD). Absorption of radioactivity was 51.9 (+OR-) 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney. The latter process appeared to be both active and saturable. At serum concentrations above 100 mcg/mL reabsorption approached its maximal capacity; renal clearance was directly dependent on glomerular filtration and free-fraction in the serum. At lower serum concentrations, changes in f(,u) had little effect on renal clearance with tubular reabsorption being the predominant determinant of cefixime's excretion.;As part of a range finding safety study for cefixime, high intravenous doses were administered to dogs. Pharmacokinetic-toxicokinetic analysis suggested that the resultant serum concentrations saturated protein binding and tubular reabsorption processes in a dose-dependent manner. Drug elimination approached that of the glomerular filtration rate while tissue exposure to cefixime was increased at the higher doses.;A deposition study was conducted to examine the relationship between serum and selected organ concentrations of cefixime and to identify any unusual patterns of drug uptake which could influence the drug's safety evaluation. Following a single intravenous dose, drug related radioactivity declined parallel to declining serum concentrations (half-life (t 1/2) (TURN) 12 hours). Additionally, an excellent correlation was observed between serum and tissue concentrations of the drug suggesting that good estimates of target organ drug concentrations can be made based solely on serum concentration data. |
