Ciprofloxacin CYP1A2 Inhibition Classification
Ciprofloxacin is classified as a moderate inhibitor of CYP1A2, not a strong inhibitor. 1
FDA Drug Label Classification
The FDA-approved ciprofloxacin drug label explicitly states that "ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism" and that "coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events." 1 However, the label does not classify it as a "strong" inhibitor, which is consistent with moderate inhibition. 1
Clinical Evidence Supporting Moderate Classification
Theophylline Interaction Data
- Ciprofloxacin inhibits theophylline metabolism (a CYP1A2 substrate) and can cause clinical toxicity, but the magnitude of inhibition is variable and moderate. 2
- In controlled studies, ciprofloxacin reduced theophylline oral clearance by only 19% on average, though individual variability ranged from minimal (4.4% reduction) to more substantial (30% reduction). 3
- This degree of inhibition (approximately 20-30% reduction in clearance) is consistent with moderate rather than strong CYP1A2 inhibition. 3
Clozapine Interaction Data
- Ciprofloxacin 250 mg twice daily increased serum clozapine concentrations by 29% and N-desmethylclozapine by 31%, demonstrating moderate inhibition. 4
- Even at higher doses, ciprofloxacin doubled clozapine concentrations in some patients, but this represents moderate rather than strong inhibition (strong inhibitors typically increase substrate levels 5-fold or more). 5
In Vitro Enzyme Studies
- In vitro studies using human liver microsomes demonstrated that ciprofloxacin showed "weak inhibition" of CYP1A2 activity with an IC50 of 135 micromol/L. 6
- This IC50 value is substantially higher than what would be expected for a strong inhibitor, supporting its classification as a moderate inhibitor. 6
Comparison with Other Fluoroquinolones
- Levofloxacin, gatifloxacin, and moxifloxacin do not significantly affect theophylline metabolism or CYP1A2 activity, demonstrating negligible CYP1A2 inhibition. 2, 6
- Ciprofloxacin is the only fluoroquinolone with clinically relevant CYP1A2 inhibitory activity, but this activity remains in the moderate range. 2, 6
Clinical Implications of Moderate Inhibition
- Dose adjustments are required when ciprofloxacin is combined with CYP1A2 substrates like tizanidine (contraindicated), theophylline (monitor levels and reduce dose), and drugs metabolized by CYP1A2 such as clozapine. 7, 1
- The American College of Clinical Pharmacology recommends reducing doses of CYP3A4 substrates when combined with ciprofloxacin as a moderate CYP3A4 inhibitor, and similar caution applies to CYP1A2 substrates. 7
- Therapeutic drug monitoring is recommended for narrow therapeutic index drugs metabolized by CYP1A2 when used with ciprofloxacin. 2, 1
Important Caveats
- While classified as moderate, ciprofloxacin's inhibitory effect shows significant inter-individual variability, with some patients experiencing minimal inhibition and others showing more pronounced effects. 3
- The clinical significance depends on the specific CYP1A2 substrate involved—drugs with narrow therapeutic indices (theophylline, tizanidine, clozapine) require particular caution even with moderate inhibition. 1, 4, 5, 8
- Ciprofloxacin's inhibition of CYP1A2 is dose-dependent, with higher doses producing more pronounced effects. 4, 5