Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2
Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2
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DOI：
10.1016/s0009-9236(99)70105-0
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发表时间：
1999-03-01
影响因子：
6.7
通讯作者：
Sörgel, F
中科院分区：
文献类型：
--
作者：
Kinzig-Schippers, M;Fuhr, U;Sörgel, F
背景与目的：据报道，培氟沙星在体内可引起临床相关的茶碱代谢抑制，但在体外培氟沙星仅是细胞色素P450 CYP1A2的弱抑制剂，介导主要的茶碱生物转化。因此，我们进一步表征了培氟沙星和CYP1A2之间的相互作用。方法：在12名健康的年轻志愿者中进行了一项随机的3期转换研究，研究培氟沙星或依诺沙星（400 mg，每天2次）与咖啡因（183 mg，每天1次）之间的稳态相互作用，咖啡因是一种有效的CYP1A2标志物。在第五次给药后对咖啡因的药代动力学进行了评估。我们在人肝微粒体中研究了培氟沙星和诺氟沙星对咖啡因3-去甲基化（体外CYP1A2探针）的影响，并用选择性抑制剂鉴定介导培氟沙星N-4'-去甲基化的酶。结果：在体内研究中，基于方差分析（anova）的点估计（90%置信区间[CI]），有和没有联合给药培氟沙星的咖啡因药代动力学比值的最大稳态血浆浓度为1.11 (C-max,C-ss, 90% CI， 0.99至1.26)，总清除率为0.53 (CLt,ss, 90% CI， 0.49至0.58)，β相分布体积为1.04 (V(d) β；90% CI, 0.96 ~ 1.13)。依诺沙星的C-max、C-ss值为1.99 (90% CI, 1.77 ~ 2.23)， CLt、ss值为0.17 (90% CI, 0.16 ~ 0.19)， V(d) β值为1.01 （90% CI, 0.90 ~ 1.13）。因此，培氟沙星导致咖啡因清除率降低2倍，依诺沙星导致咖啡因清除率降低2倍。在体外，诺氟沙星和培氟沙星对CYP1A2具有竞争性抑制作用，抑制常数（K-i）分别为0.1和1 mmol/L， CYP1A2是唯一对培氟沙星N-4'-去甲基化有相关贡献的酶（约50%）。结论：依诺沙星和较小程度的培氟沙星可能引起与CYP1A2底物进一步的临床相关相互作用。这些数据表明，培氟沙星相互作用部分是由其主要代谢物诺氟沙星介导的。
Background and objectives: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2.Methods: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme(s) that mediate pefloxacin N-4'-demethylation with selective inhibitors.Results: For the in vivo study, ANOVA-based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steady-state plasma concentrations (C-max,C-ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (V(d)beta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for C-max,C-ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for V(d)beta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 2-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (K-i) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation.Conclusions: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin.