Background: Intestinal absorption of levofloxacin (LFX) is decreased by the concomitant administration of antacids due to the formation of insoluble chelate complexes with various metal cations. Methods: The following four ester prodrugs of LFX—cilexetil ester (LFX-CLX), medoxomil ester (LFX-MDX), ethoxycarbonyl 1-ethyl hemiacetal ester (LFX-EHE) and pivaloyloxymethyl ester (LFX-PVM) — were synthesized. Then, the lipophilicity, in vitro chelate formation with aluminum chloride (AlCl3), chemical and enzymatic stability, minimum inhibitory concentrations (MICs) against some bacteria, and the efficacy in preventing chelate formation of prodrugs with aluminum hydroxide (Al(OH)3) in rabbits were evaluated. Results: The synthesized ester prodrugs of LFX exhibited high purity and higher lipophilicities than LFX depending on the ester moieties. MICs of the prodrugs against S. aureus, E. coli, and P. aeruginosa were more than 10 times higher than those of LFX. Prodrugs were stable chemically but unstable enzymatically and generated LFX in biological specimens. When AlCl3 solution was mixed with LFX solution in vitro, insoluble chelate complex was formed immediately. In rabbits, co-administration of Al(OH)3 with LFX reduced the oral bioavailability of LFX by approximately 40%. In contrast, no precipitation was observed when AlCl3 solution was mixed with each prodrug solution in vitro, and co-administration of Al(OH)3 exerted no significant effect on the oral bioavailability of LFX when each prodrug was administered in rabbits. Conclusion: The ester prodrug approach of LFX could be a feasible strategy for avoiding chelate formation with aluminum ion in vivo.

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New chelating resins immobilizing carboxymethylated polyallylamine (CM-PAA) were prepared by immobilizing PAAs with some molecular weights on methacrylate resins and then carboxymethylating a part of amino groups in the PAAs using various amounts of sodium monochloroacetate. The molecular weight of PAA barely affected both the amount of PAA immobilized on the resin and the relationship between the carboxymethylation (CM) rate and the ratio of the amount of monochloroacetate used in the CM step. The selectivity of CM-PAA resin for solid-phase extraction of trace elements was almost the same as that of a resin immobilizing carboxylymethylated polyethyleneimine; 10 elements, namely Cd, Co, Cu, Fe, Mo, Ni, Pb, Ti, V, and Zn, could be quantitatively recovered over a wide pH range and alkali and alkaline earth elements were scarcely extracted under acidic and neutral conditions. The CM-PAA resin was applicable to the separation and preconcentration of the elements in a certified reference material (Waste Water, EU-L-1) and a real environmental water sample (ground water). Keywords Chelating resin immobilizing carboxymethylated polyallylamine; solid-phase extraction; trace element; selectivity; environmental water sample acid, namely NOBIAS Chelate PA-1 (Hitachi High-Tech Fielding), 5-19 InertSep ME-2 (GL Science), 20 and Presep PolyChelate (FUJIFILM Wako Pure Chemical), 5,13,21-28 have been developed and the application of these resins for solid-phase extraction of trace elements in environmental samples has recently increased. These resins scarcely extract alkali and alkaline earth elements, which are sometimes contained at high concentration in various environmental samples and are often interfered with the determination of trace elements using atomic spectroscopy, under acidic and neutral conditions. 5,20 The selectivity of such chelating resins has been studied using chelating resins immobilizing Analytical Sciences