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

• Published in: Clinical pharmacology and therapeutics 1999-03, Vol.65 (3), p.262-274
• Main Authors: Kinzig‐Schippers, Martina, Fuhr, Uwe, Zaigler, Michael, Dammeyer, Jörg, Rüsing, Guido, Labedzki, Andreas, Bulitta, Jürgen, Sörgel, Fritz
• Format: Article
• Language: English
• Subjects: Adult; Anti-Infective Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Area Under Curve; Biological and medical sciences; Caffeine - pharmacokinetics; Central Nervous System Stimulants - pharmacokinetics; Cross-Over Studies; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP1A2 Inhibitors; Drug Interactions; Enoxacin - pharmacology; Female; Humans; Male; Medical sciences; Methylation - drug effects; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Pefloxacin - pharmacology; Pharmacology. Drug treatments; Reference Values
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(99)70105-0

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 (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 β‐phase distribution volume (Vd β; 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 Vd β (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. Clinical Pharmacology & Therapeutics (1999) 65, 262–274; doi: