Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs.
We examined inhibitory effects of ofloxacin (OFX), orbifloxacin (OBFX), ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX) on cytochrome P-450 1A (CYP1A) activities using hepatic microsomes from four beagle dogs. Ethoxyresorufin O-de-ethylation was referred as CYP1A activities. All the fluoroquinolones inhibited the reaction in a noncompetitive manner. The determined inhibitory constants were the followings; 10.1 +/- 3.8 mM for OFX, 6.43 +/- 2.01 mM for OBFX, 0.726 +/- 0.134 mM for CFX, 4.06 +/- 1.19 mM for EFX and 4.75 +/- 1.63 mM for NFX respectively. As these values are >100-fold of plasma concentrations after a clinical single dose of the fluoroquinolones, it is suggested that the inhibitory effect on CYP1A activities is not so high to elicit drug-drug interaction with CYP1A substrates, when these fluoroquinolones are co-administered. Mechanism based inhibition was also examined in this study. Of the five fluoroquinolones examined, OFX, OBFX and CFX had this inhibition manner. As this inhibition is irreversible, inhibitory effects of the three fluoroquinolones may accumulate, when they are repeatedly administered. Therefore, OFX, OBFX and CFX may result in substantial drug-drug interaction with a CYP1A substrate even in clinical states. As EFX is metabolized to CFX in the body, it may also have the same possibility.
Regmi
N L
NL
Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
Abd El-Aty
A M
AM
Kuroha
M
M
Nakamura
M
M
Shimoda
M
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004285:Dogs; D004347:Drug Interactions; D000077422:Enrofloxacin; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D009643:Norfloxacin / Q000008:administration & dosage / Q000494:pharmacology; D015242:Ofloxacin / Q000008:administration & dosage / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077422:Enrofloxacin; D002939:Ciprofloxacin; C095163:orbifloxacin; D015242:Ofloxacin; D019363:Cytochrome P-450 CYP1A1; D009643:Norfloxacin