Document Detail

Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism.
MedLine Citation:
PMID:  15592331     Owner:  NLM     Status:  MEDLINE    
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.
Marika T Granfors; Janne T Backman; Mikko Neuvonen; Pertti J Neuvonen
Publication Detail:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  76     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-13     Completed Date:  2005-01-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  598-606     Citation Subset:  AIM; IM    
Department of Clinical Pharmacology, University of Helsinki, FIN-00290 Helsinki, Finland.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Anti-Infective Agents / pharmacology*
Area Under Curve
Blood Pressure / drug effects
Caffeine / pharmacology
Chromatography, High Pressure Liquid
Ciprofloxacin / pharmacology*
Clonidine / analogs & derivatives*,  pharmacokinetics*,  pharmacology*
Cytochrome P-450 CYP1A2 / antagonists & inhibitors*
Enzyme Inhibitors*
Heart Rate / drug effects
Muscle Relaxants, Central / pharmacokinetics*,  pharmacology*
Phosphodiesterase Inhibitors / pharmacology
Reg. No./Substance:
0/Anti-Infective Agents; 0/Enzyme Inhibitors; 0/Muscle Relaxants, Central; 0/Phosphodiesterase Inhibitors; 4205-90-7/Clonidine; 51322-75-9/tizanidine; 58-08-2/Caffeine; 85721-33-1/Ciprofloxacin; EC P-450 CYP1A2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.
Next Document:  Bergamottin contribution to the grapefruit juice-felodipine interaction and disposition in humans.