Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog

Wallis, Steven C., Charles, Bruce G., Gahan, Lawrence R., Filippich, Lucio J., Bredhauer, Megan G. and Duckworth, Paul A. (1996) Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog. Journal of Pharmaceutical Sciences, 85 8: 803-809. doi:10.1021/js960087f


Author Wallis, Steven C.
Charles, Bruce G.
Gahan, Lawrence R.
Filippich, Lucio J.
Bredhauer, Megan G.
Duckworth, Paul A.
Title Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog
Journal name Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 1520-6017
0022-3549
Publication date 1996-08-01
Sub-type Article (original research)
DOI 10.1021/js960087f
Volume 85
Issue 8
Start page 803
End page 809
Total pages 7
Place of publication Hoboken, NJ, U. S. A.
Publisher Wiley-Liss
Language eng
Subject 0301 Analytical Chemistry
0302 Inorganic Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract
The formation constants of the fluoroquinolones norfloxacin and ciprofloxacin with Mg2+ (log β1 = 2.97(4), log β2 = 5.6(2)), Zn2+ (log β1 = 3.77(2), log β2 = 7.59(3)), and Fe2+ (log β1 = 3.99(5), log β2 = 7.2(5)) were determined by potentiometric titration. The pH at which precipitation occurred in the titration solutions was compared for the metal ions Ca2+, Mg2+, Zn2+, Fe2+, Cu2+, and Al3+. The formation constants were used to predict a rank order of metals that may be expected to hinder the gastrointestinal absorption of the fluoroquinolones, in vivo. The effects of metal ions on the pharmacokinetics of orally-administered norfloxacin in the dog were investigated. Norfloxacin (12 mg/kg) was administered alone or with equimolar doses of each of the chloride salts of Ca2+, Mg2+, Zn2+, Fe2+, and Al3+. Statistically significant reductions in serum norfloxacin concentrations were observed after analysis by HPLC. The Cmax was reduced 29-85%, while the area under the norfloxacin serum concentration-time curve (AUC0-∞) was reduced by 29-79%. The extent of the reduction in AUC0-∞ was correlated with the magnitude of the formation constant of the 1:1 norfloxacin:metal chelate complex for the divalent metal ions. On coadministration of 12 mg/kg norfloxacin with various doses of Mg2+ and (chloride) the AUC0-∞and Cmax decreased with increasing Mg2+ dose. The interaction peaked at a Mg2+:norfloxacin ratio of 1:2, suggesting the formation of a 1:2 Mg:norfloxacin complex. Formation constant data were used to simulate the percentage of norfloxacin complexed at pH 6.5. Combinations of metal ion and norfloxacin which result in only a small extent (<20%) of norfloxacin complex formation can result in relatively large decreases in oral bioavailability of this antimicrobial agent.
Keyword Metal-Ion Complexation
Ferrous Sulfate
Flouroquinolone Antimicrobials
Physicochemical Properties
Absorption
Ciprofloxacin
Inhibition
Antacids
Sucralfate
Ofloxacin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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