Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism

Clin Pharmacol Ther. 2004 Dec;76(6):598-606. doi: 10.1016/j.clpt.2004.08.018.


Background and objective: Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine.

Methods: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity.

Results: Ciprofloxacin increased the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (-35 mm Hg versus -15 mm Hg, P = .001), diastolic blood pressure (-24 mm Hg versus -11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC(0-infinity) of tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change.

Conclusions: Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Infective Agents / pharmacology*
  • Area Under Curve
  • Blood Pressure / drug effects
  • Caffeine / pharmacology
  • Chromatography, High Pressure Liquid
  • Ciprofloxacin / pharmacology*
  • Clonidine / analogs & derivatives*
  • Clonidine / pharmacokinetics*
  • Clonidine / pharmacology*
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Enzyme Inhibitors*
  • Half-Life
  • Heart Rate / drug effects
  • Humans
  • Muscle Relaxants, Central / pharmacokinetics*
  • Muscle Relaxants, Central / pharmacology*
  • Phosphodiesterase Inhibitors / pharmacology


  • Anti-Infective Agents
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Enzyme Inhibitors
  • Muscle Relaxants, Central
  • Phosphodiesterase Inhibitors
  • Caffeine
  • Ciprofloxacin
  • tizanidine
  • Clonidine