Synthesis and properties of N-nicotinoyl-2-(5-fluorouracil-1-yl)-D,L-glycine ester as a prodrug of 5-fluorouracil for rectal administration.

N-Nicotinoyl-2-(5-fluorouracil-1-yl)-D,L-glycine (NFG) methyl-(NFGM), ethyl-(NFGE) and isopropyl esters (NFGIp) were synthesized and their potential as a prodrug of 5-fluorouracil (5-FU) for rectal administration was investigated. Chemical conversion proceeded either by elimination of (5-FU) or by hydrolysis of ester group. 5-FU was released from NFGIp, NFGE and NFGM 90.5%, 71.3% and 48.5% of the dose, respectively, in 80% human plasma and 79.8%, 56.3% and 31.6%, respectively, in pH 7.4 buffer solution after 48 h of incubation at 37 degrees C. Release of 5-FU occurred mainly from NFG esters but very slightly from NFG, which suggested that release of 5-FU was greatly dependent on the stability of the ester group against hydrolysis. Solubility (M) in pH 7.4 buffer solution was 0.13, 0.09 and 0.04 and apparent partition coefficient in 1-octanol/pH 7.4 buffer solution was 0.76, 1.61 and 4.2, respectively, for NFGM, NFGE and NFGIp, which were in the ranges suitable for rectal absorption. Plasma concentration (microg/mL) of NFGM, NFGE and NFGIp at 50 min after rectal administration to rats was 1.9, 4.6 and 6.7, respectively, and that for 5-FU was below the limit of detection. Their potential as prodrugs of 5-FU for rectal administration is suggested.