Bioavailability study of furosemide prodrugs in rats

According to the hydrolysis performance "in vitro" and lipophylicity, two Furosemide (F) prodrugs were chosen from a series of acyloxymethylesters of F synthesized previously: P1 (acetyloxymethyl-4-chloro-N-furfuryl-5-sulfamoylanthranilate ) and P4 (pivaloyloxymethyl-4-chloro-N-furfuryl-5-sulfamoylanthranilate+ ++). The bioavailability studies were assayed over two groups of eight male Wistar rats as a randomized two-way crossover and balanced design: group 1) a solution of P1 in propylenglycol/ethyl acetate vs an aqueous solution of F, and group 2) P1 vs. P4 solutions in oleic acid (P1#, P4#). These assays showed a better absorption performance of P1 and P4 than F, while the two prodrugs showed a similar bioavailability. The oleic acid seems to be responsible for the delay in the recovery of 50% of the total amount of F excreted in urine (T50%). When the monitoring is done in plasma after the administration of P1#, P1 was not detected as circulating prodrug. The analytical determinations of F in urine and plasma were done by high performance liquid chromatography (HPLC). From the urinary excretion data, a slope that indicates a slow elimination was found with a half-life of 12 hours approximately.