IN-VITRO AND IN-VIVO STUDY OF THE EFFECTS OF ENROFLOXACIN ON HEPATIC CYTOCHROME-P-450 - POTENTIAL FOR DRUG-INTERACTIONS

Enrofloxacin (EF; BAYTRIL, Miles) was the first fluoroquinolone antimi crobial to be used in veterinary medicine in the: US. In humans, fluor oquinolones hinder the metabolism of other clinically important drugs through inhibition of hepatic cytothrome P-450(1)s (P450). Similar int eractions are suspected in animals. In this study, we characterized th e ability of EF to modify the enzymatic activity of the P450 IA and II B families. In an in vitro experiment, the inhibition of P450 reductas e by EF was assessed by measuring the NADPH-cytochrome c reductase act ivity, and the inhibition of P4501A1, IA2 and IIB by 0.25, 0.5 and 1.0 mM EF was studied, respectively, by measuring the ethoxy (EROD), meth oxy (MROD) and pentoxy (PROD) O-dealkylation activities In rat liver m icrosomes. NADPH-cytochrome c reductase was not affected. Enrofloxacin induced a strong, concentration-dependent inhibition of P4501A1 and I A2. in an in vivo experiment, the effects of 5 administrations of 5 (E F5), 25 (EF25) or 100 (EF100) mg/kg/d were assessed in rats, The liver cytochrome b5 and total P450 content was assayed by spectrophotometri c measurements; P450IA and P450IIB isozyme contents were evaluated by immunoblotting with isozyme specific monoclonal antibodies, and by mea suring MROD, EROD and PROD activities A slight induction of P450IIB1 a nd IIB2 expression and activity (140% of controls) was only present af ter EF5 treatment, We concluded that EF directly inhibits P450IA1 and IA2 and advise caution whendrugs metabolized extensively by these P450 isozymes are administered in association with EF. The slight stimulat ion of the P450IIB subfamily is not a concern at the recommended thera peutic dose of 5 mg EF/kg.