title: Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2.
abstract: OBJECTIVE
  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.
authors: Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany.
authors: M
authors: M
authors: Kinzig-Schippers
authors: U
authors: U
authors: Fuhr
authors: M
authors: M
authors: Zaigler
authors: J
authors: J
authors: Dammeyer
authors: G
authors: G
authors: Rüsing
authors: A
authors: A
authors: Labedzki
authors: J
authors: J
authors: Bulitta
authors: F
authors: F
authors: Sörgel
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004347:Drug Interactions; D015365:Enoxacin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D015366:Pefloxacin / Q000494:pharmacology*; D012016:Reference Values
chemical_list: D000890:Anti-Infective Agents; D000697:Central Nervous System Stimulants; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D015366:Pefloxacin; D015365:Enoxacin; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2