Fuhr U, Wolff T, Harder S, Schymanski P, Staib A H
Abt. Klinische Pharmakologie, Universitätsklinik Frankfurt, F.R.G.
Drug Metab Dispos. 1990 Nov-Dec;18(6):1005-10.
Inhibitory effects of the quinolone antibiotics ofloxacin, lomefloxacin, pipemidic acid, ciprofloxacin, and enoxacin on caffeine metabolism were examined in vitro with human liver microsomes of four donors. All drugs competitively inhibited the activity of 3-demethylation, the major pathway of caffeine metabolism. Enoxacin, ciprofloxacin, and pipemidic acid were strong inhibitors exhibiting Ki values between 0.1 and 0.2 mM. Lomefloxacin and ofloxacin had moderate effects with Ki values of 1.2 and 3.6 mM, respectively. The rate of caffeine 7-demethylation (which amounted to about 25% of that for 3-demethylation) was only slightly affected by the quinolones. Minor, but inconsistent, effects were found on 8-oxidation to 1,3,7-trimethyluric acid. The results indicate that the reduction of caffeine clearance by concomitant quinolone application observed in vivo is primarily due to a competitive interaction of the inhibiting quinolones with the cytochrome P-450 isoenzyme(s) mediating caffeine demethylation.
利用来自四名供体的人肝微粒体在体外研究了喹诺酮类抗生素氧氟沙星、洛美沙星、吡哌酸、环丙沙星和依诺沙星对咖啡因代谢的抑制作用。所有药物均竞争性抑制咖啡因代谢的主要途径——3-去甲基化的活性。依诺沙星、环丙沙星和吡哌酸是强抑制剂，其Ki值在0.1至0.2 mM之间。洛美沙星和氧氟沙星的作用中等，Ki值分别为1.2和3.6 mM。咖啡因7-去甲基化的速率（约占3-去甲基化速率的25%）仅受到喹诺酮类药物的轻微影响。在8-氧化生成1,3,7-三甲基尿酸方面发现了微小但不一致的影响。结果表明，体内观察到的喹诺酮类药物联合应用导致咖啡因清除率降低主要是由于抑制性喹诺酮类药物与介导咖啡因去甲基化的细胞色素P-450同工酶之间的竞争性相互作用。
