Interaction of Quinolones with Metal Cations in Aqueous Solution

Abstract

Quinolones are a group of potent antibacterial agents. Many reports show that oral absorption of quinolones is reduced by coadministration of metallic preparations. For better understanding of this phenomenon, we investigated the complex formations of quinolones (DU-6859a, DV-7751a, DR-3862, levofloxacin) with various metal cations by pH titrations, NMR and spectrophotometry. Several metal complexes including hydroxo species were confirmed by pH titrations. The order of stability constants among trivalent metal cations was Fe³⁺>Al³⁺, and those among devalent metal cations was Cu²⁺>Fe²⁺>Zn²⁺>Mg²⁺>Ca²⁺. The differences in stability constants among quinolones were not as large. Complex structures and metal complex formation equilibria in aqueous solution were proposed. Quinolones were belived to bind metal cations through carboxyl group and carbonyl group of the quinolone ring, and these equilibria show that there are two types of deprotonation reactions from metal complex : the several Fe³⁺ complexes and Al³⁺ complexes liberate protons from coordinated water molecules under acidic to neutral conditions, while the other complexes liberate protons from amine groups under neutral to alkaline conditions. Moreover, quantitative behavior of metal complex in aqueous solution has been demonstrated by simulation for the first time. The simulation especially showed that quinolones interact with Al³⁺ in the stomach, but with Mg²⁺ in the intestines when coadministered with antacid containing Al³⁺ and Mg²⁺. These results suggest that the complex formation of quinolones with metal cations is an important factor affecting absorption of the former in the gastrointestinal tract.