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

作　　者：Syed Sher Shah Sadaat Nasrin Stankzi Mohammad Monir Tawfeeq Farid Ahmad Tanin Amanullah Aziz Kazuki Sasaki Syed Sher Shah Sadaat;Nasrin Stankzi;Mohammad Monir Tawfeeq;Farid Ahmad Tanin;Amanullah Aziz;Kazuki Sasaki(Department of Clinic, Faculty of Veterinary Science, Kabul University, Kabul, Afghanistan;Department of Pre Clinic, Faculty of Veterinary Science, Kabul University, Kabul, Afghanistan;Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan)

机构地区：[1]Department of Clinic, Faculty of Veterinary Science, Kabul University, Kabul, Afghanistan [2]Department of Pre Clinic, Faculty of Veterinary Science, Kabul University, Kabul, Afghanistan [3]Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan

出　　处：《Open Journal of Veterinary Medicine》2020年第12期219-237,共19页兽医学（英文）

摘　　要：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 <i>in vitro</i> 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 (K_i) 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.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 <i>in vitro</i> 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 (K_i) 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.

关 键 词：Several Fluoroquinolones CYP Inhibitors EROD MIDAZOLAM MICROSOMES 

分 类 号：R96[医药卫生—药理学]