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 antimicrobial to be used in veterinary medicine in the US. In humans, fluoroquinolones hinder the metabolism of other clinically important drugs through inhibition of hepatic cytochrome P-450's (P450). Similar interactions are suspected in animals. In this study, we characterized the ability of EF to modify the enzymatic activity of the P450 IA and IIB families. In an in vitro experiment, the inhibition of P450 reductase by EF was assessed by measuring the NADPH-cytochrome c reductase activity, and the inhibition of P450IA1, IA2 and IIB by 0.25, 0.5 and 1.0 mM EF was studied, respectively, by measuring the ethoxy (EROD), methoxy (MROD) and pentoxy (PROD) O-dealkylation activities in rat liver microsomes. NADPH-cytochrome c reductase was not affected. Enrofloxacin induced a strong, concentration-dependent inhibition of P450IA1 and IA2. In an in vivo experiment, the effects of 5 administrations of 5 (EF5), 25 (EF25) or 100 (EF100) mg/kg/d were assessed in rats. The liver cytochrome b5 and total P450 content was assayed by spectrophotometric measurements; P450IA and P450IIB isozyme contents were evaluated by immunoblotting with isozyme specific monoclonal antibodies, and by measuring MROD, EROD and PROD activities. A slight induction of P450IIB1 and IIB2 expression and activity (140% of controls) was only present after EF5 treatment. We concluded that EF directly inhibits P450IA1 and IA2 and advise caution when drugs metabolized extensively by these P450 isozymes are administered in association with EF. The slight stimulation of the P450IIB subfamily is not a concern at the recommended therapeutic dose of 5 mg EF/kg.
Vancutsem
P M
PM
Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, NY 14853, USA.
Babish
J G
JG
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004591:Electrophoresis, Polyacrylamide Gel; D000077422:Enrofloxacin; D024841:Fluoroquinolones; D015151:Immunoblotting; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009245:NADH Dehydrogenase / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; D000077422:Enrofloxacin; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D009245:NADH Dehydrogenase