A COMPREHENSIVE MODEL FOR ENROFLOXACIN TO CIPROFLOXACIN TRANSFORMATION AND DISPOSITION IN DOG

The pharmacokinetics of enrofloxacin and ciprofloxacin, its major acti ve metabolite, were determined in dog after oral and intravenous admin istrations of enrofloxacin and intravenous infusion of ciprofloxacin. A comprehensive model of enrofloxacin and ciprofloxacin disposition wa s constructed to investigate the extent of enrofloxacin to ciprofloxac in transformation and the influence of the hepatic first-pass effect o n the parent compound oral bioavailability. Plasma levels were measure d using a validated HPLC method. Enrofloxacin and ciprofloxacin plasma concentration data were fitted simultaneously using a set of differen tial equations describing a six-compartment model (two compartments fo r 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. Th e fitted parameters obtained from the model were used to calculate pla sma clearances (0.729 +/- 0.212 L/h/kg for enrofloxacin, 0.468 +/- 0.0 94 L/h/kg for ciprofloxacin), distribution volumes (2.45 +/- 0.49 L/kg for enrofloxacin, 1.92 +/- 0.33 L/kg for ciprofloxacin), mean residen ce times (3.47 +/- 0.78 h for enrofloxacin, 4.20 +/- 0.82 h for ciprof loxacin), and the fractions of enrofloxacin metabolized to ciprofloxac in after intravenous and oral administrations of enrofloxacin. It was shown that enrofloxacin was largely metabolized to ciprofloxacin and t hat the fractions of metabolized enrofloxacin were similar after intra venous and oral administrations of enrofloxacin (40.44 +/- 10.08 and 4 0.17 +/- 8.33%, respectively), the hepatic first-pass effect being low (7.15 +/- 1.99%).