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

2004; Wiley; Volume: 76; Issue: 6 Linguagem: Inglês

10.1016/j.clpt.2004.08.018

1532-6535

Marika T. Granfors, Janne T. Backman, Mikko Neuvonen, Pertti J. Neuvonen,

Pharmacological Effects and Toxicity Studies

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-∞)] 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-∞) 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. Clinical Pharmacology & Therapeutics (2004) 76, 598–606; doi: 10.1016/j.clpt.2004.08.018