Development of hemiacetal esterified levofloxacin to prevent chelation with metal-containing drugs.

Abstract

To avoid the chelate formation between levofloxacin (LVFX) and aluminium hydroxide in gastrointestinal tract, an ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) was synthesised as a prodrug. The effects of aluminium hydroxide on the bioavailability of LVFX following oral administration of LVFX-EHE were investigated in rats. Furthermore, the effects of aluminium hydroxide on small intestinal absorption of LVFX and LVFX-EHE when subjected to a hydrolysis experiment using in situ everted gut sac were investigated, and the minimal inhibitory concentrations (MICs) of LVFX and LVFX-EHE for various intestinal bacteria were measured. When LVFX-EHE was co-administered with and without aluminium hydroxide, the AUC0-4 h values of LVFX hydrolysed from LVFX-EHE were similar to that of LVFX alone. In everted gut sac experiments, LVFX-EHE was efficiently absorbed even in the presence of aluminium ions after 1 h of incubation, whereas the absorption of LVFX decreased significantly in the presence of aluminium ions. MIC values of LVFX-EHE were far higher than LVFX. This study suggests the benefit of ethoxycarbonyl 1-ethyl hemiacetal esterification of the carboxyl group of new quinolone as a prodrug which is able to avoid chelate formation.