Abstract
Eight amino acid esters of metronidazole were synthesized and evaluated as potential water-soluble prodrugs with the aim of developing preparations suitable for intravenous injection. Hydrochloride salts of all the esters exhibited a water-solubility greater than 20%. Rates of hydrolysis of the esters at 37°C in 80% huma plasma were studied. Complete reversion to metronidazole was observed as determined by HPLC and in all cases the hydrolysis followed strict first-order kinetics. The susceptibility of the various esters to undergo enzymatic hydrolysis varied widely, the observed half-lives in 80% human plasma being 8 min (N-propylglycinate), 12 min (N,N-dimethylglycinate), 30 min (4-morpholinoacetate), 41 minn (glycinate), 46 min (3-dimethylaminopropionate), 207 min (3-aminopropionate), 334 min (4-dimethylaminobutyrate) and 523 min (4-methyl-l-piperazinoacetate). It was concluded that due to its facile enzymatic conversion in plasma or blood, excellent solubility properties (> 50% w/v) and case of synthesis and purification, the hydrochloride of metronidazole N,N-dimethylglycinate appears to be the most promising prodrug candidate as a patenterai delivery form of metronidazole.
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