Effect of aluminium ion on bioavailability of levofloxacin following oral administration of cilexetil ester of levofloxacin as prodrug in rats.

A prodrug of levofloxacin (LVFX), cilexetil ester of LVFX (LVFX-CLX), was synthesized to examine whether the prodrug can avoid chelate formation with metal cations in the gastrointestinal tract. LVFX-CLX exhibited a 10-times higher partition coefficient than LVFX. In vitro, LVFX was precipitated by 76.1% in the presence of a 10-times higher concentration of aluminium chloride (Al), but LVFX-CLX was not. LVFX-CLX was rapidly hydrolyzed enzymatically by rat plasma, intestinal mucosal and liver homogenates at 37 °C, but not by pancreatic enzymes and luminal fluid. The minimum inhibitory concentration values of LVFX-CLX against and were far higher than that of LVFX. In rats, area under the plasma concentration-time curve from zero to 4 h (AUC) of LVFX after oral administration of LVFX-CLX was 1.34-fold higher than that after LVFX, though it did not reach significance level. Co-administration of Al with LVFX and LVFX-CLX in rats decreased AUC of plasma LVFX by 75% and 60%, respectively, however, the AUC of plasma LVFX after co-administration of LVFX-CLX and Al was 2.2-times higher than that after co-administration of LVFX and Al. These results suggested that the use of LVFX-CLX may reduce the modulation of intestinal microflora caused by LVFX and the suppressive effect of Al on intestinal absorption of LVFX.