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

Background and objectives: Pefloxacin is reported to cause clinically relev ant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main the ophylline biotransformation. We therefore further characterized the interac tion between pefloxacin and CYP1A2. Methods: A randomized 3-period change-over study was conducted in 12 health y young volunteers on the steady-state interactions between pefloxacin or e noxacin (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 ef fect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme(s) that mediate pefloxacin N-4'-d emethylation 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 witho ut pefloxacin coadministration were 1.11 for maximal steady-state plasma co ncentrations (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 vol ume (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-f old decrease in caffeine clearance, and enoxacin caused a 2-fold decrease i n caffeine clearance. In vitro, norfloxacin and pefloxacin competitively in hibited 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 clinicall y relevant interactions with further CYP1A2 substrates. The data suggest th at the pefloxacin interaction is partly mediated by its major metabolite no rfloxacin.