EFFECTS OF ALUMINUM-CONTAINING ANTACID ON BIOAVAILABILITY OF OFLOXACIN FOLLOWING ORAL-ADMINISTRATION OF PIVALOYLOXYMETHYL ESTER OF OFLOXACIN AS PRODRUG

We newly synthesized a pivaloyloxymethyl ester of ofloxacin (OFLX-PVM) as prodrug in order to avoid the chelate formation between new quinol one and metal cations such as Al3+, Mg2+, Ca2+, or Fe2+ in the gastroi ntestinal tract. This compound was rapidly hydrolyzed in an incubation experiment by 43% in plasma, by 92% in small intestinal mucosal homog enates, and by 97% in liver homogenates during 0.5 h incubation, but w as resistant to hydrolysis by pancreatic enzymes. In everted gut sac e xperiments, this compound was efficiently absorbed even in the presenc e of aluminium ion, whereas the absorption of ofloxacin (OFLX) was dec reased significantly by the presence of aluminium ion. Minimal inhibit ory concentration (MIC) values of OFLX-PVM were far higher than OFLX. Effects of aluminium hydroxide on the oral bioavailability of OFLX and OFLX-PVM were investigated in rabbits. The area under the plasma conc entration-versus-time curve from zero to 24 h (AUC0-24 h) following or al administration of OFLX was decreased significantly by 47.6% by comb ined administration with aluminium hydroxide, but AUC0-24 h values of OFLX-PVM coadministered with and without aluminium hydroxide were simi lar to that of OFLX alone. These observations indicate that this new c ompound is likely to offer a prodrug for avoidance of interaction betw een new quinolone and metal cations.