title: Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog.
abstract: The formation constants of the fluoroquinolones norfloxacin and ciprofloxacin with Mg2+ (log beta 1 = 2.97(4), log beta 2 = 5.6(2)), Zn2+ (log beta 1 = 3.77(2), log beta 2 = 7.59(3)), and Fe2+ (log beta 1 = 3.99(5), log beta 2 = 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-infinity) was reduced by 29-79%. The extent of the reduction in AUC0-infinity 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+ (chloride) the AUC0-infinity 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.
authors.affiliation: Department of Chemistry, University of Queensland, Brisbane, Australia.
authors.forename: S C
authors.initials: SC
authors.lastname: Wallis
authors.forename: B G
authors.initials: BG
authors.lastname: Charles
authors.forename: L R
authors.initials: LR
authors.lastname: Gahan
authors.forename: L J
authors.initials: LJ
authors.lastname: Filippich
authors.forename: M G
authors.initials: MG
authors.lastname: Bredhauer
authors.forename: P A
authors.initials: PA
authors.lastname: Duckworth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002412:Cations; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004347:Drug Interactions; D009643:Norfloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011199:Potentiometry
chemical_list: D002412:Cations; D009643:Norfloxacin