A Comprehensive Model for Enrofloxacin to Ciprofloxacin Transformation and Disposition in Dog

Abstract

The pharmacokinetics of enrofloxacin and ciprofloxacin, its major active metabolite, were determined in dog after oral and intravenous administrations of enrofloxacin and intravenous infusion of ciprofloxacin. A comprehensive model of enrofloxacin and ciprofloxacin disposition was constructed to investigate the extent of enrofloxacin to ciprofloxacin transformation and the influence of the hepatic first-pass effect on the parent compound oral bioavailability. Plasma levels were measured using a validated HPLC method. Enrofloxacin and ciprofloxacin plasma concentration data were fitted simultaneously using a set of differential equations describing a six-compartment model (two compartments for each analyte, one for the liver, and one for the intestinal tract); it was assumed that only a fraction of enrofloxacin was metabolized to ciprofloxacin and that this conversion only occurred in the liver. The fitted parameters obtained from the model were used to calculate plasma clearances (0.729 +/- 0.212 L/h/kg for enrofloxacin, 0.468 +/- 0.094 L/h/kg for ciprofloxacin), distribution volumes (2.45 +/- 0.49 L/kg for enrofloxacin, 1.92 +/- 0.33 L/kg for ciprofloxacin), mean residence times (3.47 +/- 0.78 h for enrofloxacin, 4.20 +/- 0.82 h for ciprofloxacin), and the fractions of enrofloxacin metabolized to ciprofloxacin after intravenous and oral administrations of enrofloxacin. It was shown that enrofloxacin was largely metabolized to ciprofloxacin and that the fractions of metabolized enrofloxacin were similar after intravenous and oral administrations of enrofloxacin (40.44 +/- 10.08 and 40.17 +/- 8.33%, respectively), the hepatic first-pass effect being low (7.15 +/- 1.99%).