Vancutsem P M, Babish J G
Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, NY 14853, USA.
Vet Hum Toxicol. 1996 Aug;38(4):254-9.
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.
恩诺沙星（EF；拜有利，迈尔斯公司）是美国第一种用于兽医学的氟喹诺酮类抗菌药物。在人类中，氟喹诺酮类药物通过抑制肝脏细胞色素P - 450（P450）来阻碍其他临床重要药物的代谢。在动物中也怀疑有类似的相互作用。在本研究中，我们对恩诺沙星改变P450 IA和IIB家族酶活性的能力进行了表征。在体外实验中，通过测量NADPH - 细胞色素c还原酶活性来评估恩诺沙星对P450还原酶的抑制作用，并分别通过测量大鼠肝微粒体中的乙氧基（EROD）、甲氧基（MROD）和戊氧基（PROD）O - 脱烷基活性，研究0.25、0.5和1.0 mM恩诺沙星对P450IA1、IA2和IIB的抑制作用。NADPH - 细胞色素c还原酶未受影响。恩诺沙星对P450IA1和IA2产生了强烈的、浓度依赖性的抑制作用。在体内实验中，评估了以5（EF5）、25（EF25）或100（EF100）mg/kg/d的剂量给药5次对大鼠的影响。通过分光光度法测量肝脏细胞色素b5和总P450含量；通过用同工酶特异性单克隆抗体进行免疫印迹以及测量MROD、EROD和PROD活性来评估P450IA和P450IIB同工酶含量。仅在EF5治疗后出现了P450IIB1和IIB2表达及活性的轻微诱导（为对照组的140%）。我们得出结论，恩诺沙星直接抑制P450IA1和IA2，并建议当与恩诺沙星联合使用大量由这些P450同工酶代谢的药物时要谨慎。在5 mg EF/kg的推荐治疗剂量下，P450IIB亚家族的轻微刺激无需担忧。
