培氟沙星和依诺沙星与人类细胞色素P450酶CYP1A2的相互作用。

Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2.

作者信息

Kinzig-Schippers M, Fuhr U, Zaigler M, Dammeyer J, Rüsing G, Labedzki A, Bulitta J, Sörgel F

机构信息

Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany.

出版信息

Clin Pharmacol Ther. 1999 Mar;65(3):262-74. doi: 10.1016/S0009-9236(99)70105-0.

DOI:10.1016/S0009-9236(99)70105-0

PMID:10096258

Abstract

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 steadystate plasma concentrations (Cmax,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 (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) 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.

摘要

背景与目的

据报道，培氟沙星在体内可对茶碱代谢产生具有临床意义的抑制作用，但在体外，培氟沙星只是细胞色素P450 CYP1A2的弱抑制剂，而CYP1A2介导主要的茶碱生物转化。因此，我们进一步对培氟沙星与CYP1A2之间的相互作用进行了表征。

方法

对12名健康年轻志愿者进行了一项随机的3周期交叉研究，以研究培氟沙星或依诺沙星（每日两次，每次400 mg）与咖啡因（每日一次，183 mg）之间的稳态相互作用，咖啡因是一种经过验证的CYP1A2标志物。在咖啡因第五次给药后评估其药代动力学。在人肝微粒体中进行研究，以测量培氟沙星和诺氟沙星对咖啡因3-去甲基化（一种体外CYP1A2探针）的影响，并使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

对于体内研究，基于方差分析的有无培氟沙星联合给药时咖啡因药代动力学比值的点估计值（90%置信区间[CI]），最大稳态血浆浓度（Cmax,ss）为1.11（90%CI，0.99至1.26），总清除率（CLt,ss）为0.53（90%CI，0.49至0.58），β相分布容积（Vdbeta）为1.04（90%CI，0.96至1.13）。依诺沙星的相应值为，Cmax,ss为1.99（90%CI，1.77至2.23），CLt,ss为0.17（90%CI，0.16至0.19），Vdbeta为1.01（90%CI，0.90至1.13）。因此，培氟沙星使咖啡因清除率降低了2倍，依诺沙星使咖啡因清除率降低了6倍。在体外，诺氟沙星和培氟沙星竞争性抑制CYP1A2，抑制常数（Ki）值分别为0.1和1 mmol/L，并且CYP1A2是对培氟沙星N-4'-去甲基化有相关贡献（约50%）的唯一酶。