Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes

Abstract

Aim: To determine the inhibitory potential of 2 new fluoroquinolones, caderofloxacin and antofloxacin, together with 4 marketed fluoroquinolones, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin, on the activity of cytochrome P450 isoforms 1A2 (CYP1A2) and 2C9 (CYP2C9). Methods: Probe substrates, phenacetin (CYP1A2), and tolbutamide (CYP2C9) were incubated with human liver microsomes and the metabolites were analyzed by liquid chromatography/mass spectrometry using electrospray ionization in positive or negative mode. Glipizide was used as the internal standard in both modes. The inhibitory potential of fluoroquinolones on CYP1A2 and CYP2C9 was investigated. Results: The IC 50 values (μmol/L) determined with the cocktail were in agreement with individual probe substrates (α-naphthoflavone: 0.27 vs 0.26; sulfaphenazole: 0.49 vs 0.37). Ciprofloxacin showed weak inhibition on both the activity of CYP1A2 (IC 50 135 μmol/L) and CYP2C9 (IC 50 180 μmol/L), whereas levofloxacin inhibited only CYP2C9 (IC 50 210 μmol/L). Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin showed little or no inhibition on the activity of CYP1A2 or CYP2C9 when tested at comparable concentrations (0−200 mg/L). Conclusion: Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin are negligible inhibitors to CYP1A2 and CYP2C9. The in vitro system can be used as a high-throughput model to screen similar compounds for the early identification of drug-drug interaction potential.

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

“…However, the results indicate that the acute or chronic administration of caderofloxacin did not change the activity of CYP1A2. This finding agrees with a previous study, which reported that caderofloxacin is a negligible inhibitor of CYP1A2 in human microsomes [41] . In conclusion, the activity of hepatic CYP2E1 increased as a result of the elevated mRNA and protein levels of hepatic CYP2E1 induced by the chronic administration of caderofloxacin.…”

Iatrogenic Cushing’s Syndrome Following Short-Term Intranasal Steroid Use

“…Her use of 2 bottles per month is equivalent to 20 mg of dexamethasone per month which is around 0.7mg of dexamethasone per day, which is high for a 6-year-old girl. Moxifloxacin does not inhibit or stimulate the hepatic microsomal P450 system and hence has no effect on steroid metabolism (8). Since drops were used instead of nasal spray, it is likely that a significant amount would be swallowed and absorbed from the gastrointestinal tract, resulting in CS.…”

Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

“…The detailed model input parameters were also listed in Table 1. The in vitro IC50 value on the CYP1A2 measured by Zhang et al was also used for this DDI simulation [28]. Population mean age, dose, dose interval and the duration of administration of ciprofloxacin and caffeine were determined according to the regimen of the clinical DDI studies.…”