Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism.
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.
Granfors
Marika T
MT
Department of Clinical Pharmacology, University of Helsinki, FIN-00290 Helsinki, Finland.
Backman
Janne T
JT
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000494:pharmacology*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D000890:Anti-Infective Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D009125:Muscle Relaxants, Central; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D002939:Ciprofloxacin; C023754:tizanidine; D003000:Clonidine