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

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.

Copper(II) complexes of the fluoroquinolone antimicrobial ciprofloxacin. Synthesis, X-ray structural characterization, and potentiometric study.

Reaction of the fluoroquinolone antimicrobial ciprofloxacin with copper(II) nitrate in the presence of 2,2'-bipyridine resulted in the isolation of the complex [Cu(cip)(bipy) (Cl)0.7(NO3)0.3] (NO3).2H2O. Reaction of an aqueous solution of ciprofloxacin.HCl and NaCl with CuCl2 at pH 5.0 resulted in the isolation of [Cu(cip)2]Cl2.11H2O. The complex [Cu(cip) (bipy)(Cl)0.7(NO3)0.3] (NO3).2H2O crystallizes in the monoclinic space group P2(1)/n, with a = 13.955(8), b = 14.280(8), c = 14.192(6) A, beta = 93.10(4) degrees, Z = 4 with R = 0.046. The selective broadening of resonances in the 13C NMR spectrum of ciprofloxacin by the addition of Cu2+(aq) was employed to probe metal ion binding sites in the ligand. The protonation constants of norfloxacin and ciprofloxacin, and the formation constants with copper(II), were determined by potentiometric titrations at 25 degrees C. The additions of ciprofloxacin to metal to form ML and ML2 complexes exhibit stepwise formation constants of log K1 6.2(1) and log K2 11.1(3), respectively.