Inhibitory Effects of Several Fluoroquinolones on Feline CYP1A and 3A in Hepatic Microsomes

Syed Sher Shah Sadaat,Farid Ahmad Tanin,Mohammad Monir Tawfeeq,Kazuki Sasaki,Nasrin Stankzi,Amanullah Aziz

doi:10.4236/ojvm.2020.1012019

Syed Sher Shah Sadaat, Farid Ahmad Tanin + Show 4 more

Open Access

https://doi.org/10.4236/ojvm.2020.1012019

Copy DOI

Abstract

In this study, the effects of several fluoroquinolones (FQs), such as Ciprofloxacin (CPFX); Orbifloxacin (OBFX); Norfloxacin (NFX); Ofloxacin (OFX); and Enerofloxacin (EFX) on activities of both Cytochrome P450 1A (CYP1A) and Cytochrome P450 3A (CYP3A) of feline microsomes by in vitro tests were studied. Ethoxyresorufin O-deethylation (EROD) and Midazolam 1' hydroxylation and 4-hydroxylation (MDZ1'H and MDZ4H) were analyzed by High Performance Liquid Chromatography (HPLC). All the FQs inhibited the reactions by a competitive or noncompetitive and irreversible manner. The inhibitory constants (Ki) were as followings: CYP1A; ranged from 0.12 to 1.23 mM for NFX, OBFX, EFX, CPFX, OFX and CYP3A, for MDZ1'H; ranged from 5.8 to 35 and MDZ4H; 9 to 29 mM, respectively. As these values are higher by 24 to 200-times of given single clinical dose of serum levels after application of FQs. It indicates that if co-administrated with these FQs by reversible inhibitory manner, the inhibition of CYP1A and CYP3A effect on CYP1A and 3A actions is not very significant to cause drug interaction with above mentioned enzyme substrates. Out of the FQs tested, CPFX and NFX for CYP1A, and CPFX for CYP3A showed irreversible inhibitory effects (time-dependent), so it has been concluded that these drugs may cause drug-drug interaction by accumulation, when they are repeatedly administrated. Since EFX is biotransformed to CPFX by the liver, it could have the identical risk too.

Highlights

Cytochrome P450s (CYPs) are the most significant enzymes of phase one drug biotransformation in the liver that is important for the removal of many drugs and xenobiotic
Reversible inhibition might not effect in a drug interaction with added drugs that are substrates intended for Cytochrome P450 1A (CYP1A) enzyme
The results showed that all FQs inhibited CYP1A activity by a competitive manner except CPFX which inhibited the enzyme activity in a noncompetitive mode, where the inhibitory mode on MDZ1'H and MDZ4H reactions for Cytochrome P450 3A (CYP3A) activity by a noncompetitive manner in cats

Summary

Introduction

Cytochrome P450s (CYPs) are the most significant enzymes of phase one drug biotransformation in the liver that is important for the removal of many drugs and xenobiotic. Impairment of medication breakdown as a consequence of drug interaction, either by pharmacokinetic or pharmacodynamic; may result in some clinical complications such as harmfulness as a result of a high level plasma levels or reduced elimination. Among drug-drug interaction, there are many reports on increases in drug concentrations caused by inhibition of oxidative metabolism through CYPs. much care has been taken for the factors that alter drug biotransformation. Modifications in drug biotransformation in general enzyme induction [1] or enzyme inhibition [2] can alter the drug biotransformation. Enzyme inhibition is well predictable as a basis of clinically substantial opposing drug interaction [3] [4], since the enzyme inhibition could foremost to fatal toxicity of co-administered drugs [5]

Methods

Results

Discussion

Conclusion