Pharmacokinetics of cefixime after oral and intravenous doses in dogs: bioavailability assessment for a drug showing nonlinear serum protein binding.

Cefixime is a new oral cephalosporin which shows dose dependent absorption and concentration dependent serum protein binding in dogs. To study the absolute bioavailability of this drug in dogs, intravenous infusions of 6.25 and 25 mg/kg (each given over 2 hours), approximating the rate of appearance of the drug also given after oral dosing (12.5 and 50 mg/kg) were administered on separate occasions. The mean respective pharmacokinetic parameters obtained after the two intravenous infusions (6.25 and 25 mg/kg) were: total body clearance 4.0 and 5.2 mL/min; volume of distribution 2.2 and 2.8 L; and terminal half-lives of 6.4 hrs. Serum concentrations and area under the serum concentration time curve (AUC) after the low intravenous and oral dose were similar. At the higher doses, serum concentrations and AUC values were significantly higher after the intravenous infusion than after the oral dose. The mean absolute bioavailability (F) values after the 12.5 and 50 mg/kg oral doses using serum AUC comparisons were 52 and 58%, respectively, when calculated against the 6.25 mg/kg intravenous dose and 73 and 38%, respectively, when calculated against the 25 mg/kg intravenous dose. Based on urinary recovery data, F was 49 or 43% for the 12.5 mg/kg oral dose and 34 or 30% for the 50 mg/kg oral dose, depending on the reference intravenous dose used. These results show that because of nonlinearities in the pharmacokinetics of cefixime in the dog, comparison of AUC values obtained after oral doses to AUC values derived following intravenous administration of the drug may result in inaccurate bioavailability estimates if the concentration ranges after the two routes of administration are substantially different. Since the clearance of the drug is concentration-dependent, the absolute bioavailability of the drug must, therefore, be estimated under conditions where serum concentrations obtained after oral and intravenous doses are similar. In summary, for a drug like cefixime which shows nonlinear pharmacokinetics in the dog, estimations of absolute bioavailability, can be more accurately made using urinary excretion data.