220819-28-3Relevant articles and documents
Metronidazole twin ester prodrugs II: Non identical twin esters of metronidazole and some antiprotozoal halogenated hydroxyquinoline derivatives
Aboul-Fadl, Tarek,Mahfouz, Nadia M.
, p. 309 - 324 (2007/10/03)
New non identical twin ester prodrugs 3a-d were synthesized by linking metronidazole and some antiprotozoal halogented 8-hydroxyquinoline derivatives via dicarboxylic acid spacers with the aim of improving the therapeutic efficacy of both drugs. The synthesis necessitates the preparation of the precursor metronidazole hemisuccinate or hemiphthalate followed by estrification with the respective hydroxyquinoline derivative. To assess their suitability as prodrugs, the lipophilic properties, chemical stability as well as in vitro and in vivo enzymatic hydrolysis were investigated. The lipophilic properties, expressed as Rm values were determined using RP-TLC and showing enhanced lipophilicity as compared with the parent drugs. Hydrolysis kinetics of the prepared twin esters at 37°C using HPLC, indicated a quantitative release of the parent drugs in two step reaction (K1 and K2) via formation of metronidazole hemiesters followed by spontaneous hydrolysis of the later to metronidazole. The twin esters were adequately stable in aqueous buffer solutions than in biological media and the second rate (K2) of hydrolysis is more accelerated than the first (K1). Bioavailability study of 1-(5-chloro-7-iodoquinolin-8-yl)-4-[2-(2-methyl-5- nitro-1-H-imidazolyl)ethyl]butandioate, 3a, as well as equivalent amount of the corresponding physical mixture of metronidazole and 5-chloro 7-iodo-8- hydroxyquinoline in rabbits has shown that, the plasma level of the released metronidazole from the prodrug is higher than that resulting from the physical combination. A considerable amount of 5-chloro-7-iodo- hydroxyquinoline was detected in plasma, however, no measurable concentration of the quinoline derivative was observed in rabbit plasma from the physical mixture.
