In vivo and in vitro interactions of enrofloxacin with rabbit drug metabolizing enzymes.

The administration of enrofloxacin (ENF) to humans and dogs results in a number of clinically relevant drug interaction, which are mainly attributable to the ENF-mediated inhibition of certain P450-dependant biotransformation pathways. Despite the fact that in EU this antimicrobial is approved for use in rabbits, there is a lack of information about its possible interactions with hepatic drug metabolizing enzymes (DMEs). To this end, 15 male crossbred rabbits for meat production were divided into three groups (N=5) and respectively administered saline, 5 mg/kg (therapeutic dose) or 25 mg/kg ENF (Baytril ®) by oral gavage for 5 days. After an overnight starving, animals were sacrificed and livers were removed. Hepatic subcellular fractions were then isolated and used to determine P450 content as well as NADPH cytochrome c reductase and a panel of phase I and II DME activities including model substrates for P450 1A1/2, 2B, 3A, 2E, microsomial carboxylesterases (EST), GSH S-transferase (GST), DT-diaphorase and UDPG-transferases. Both dosages did not cause statistically significant changes, but preparation from 25 mg/kg treated animals displayed a decrease (by 25%) in the rate of the in vitro metabolism of the CYP 1A substrate ethoxy- and methoxyresorufin and in the activities of CDNB-GST and EST. When testing the same enzyme activities as to their sensitivity to ENF concentrations ranging from 0.125 to 10 mM, only CDNB-GST exhibited a marked concentration-related inhibition with a calculated IC50 of about 0.3 mM. It is concluded that the use of ENF at therapeutic doses in rabbit is unlikely to alter the hepatic DME profile significantly and hence to affect the kinetics of concurrently administered drugs. Supported by M.U.R.S.T. grants Cofin98