@article {Mahfouz:1 June 2001:0022-3573:841,
	author = "Mahfouz N.M.",
	author = "Hassan M.A.",
	title = "Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility",
	journal = "Journal of Pharmacy and Pharmacology",
	volume = "53",
	year = "1 June 2001",
	abstract = "A series of amino acid esters (<B>3a&#150;e</B>) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (<B>3a</B>) and 4-ethylpiperazinoacetate (<B>3e</B>) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (<B>3f</B>), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH7.4) and 80&#037; human plasma at 37&#176;C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t, 4&#150;16h) in aqueous phosphate solution of pH7.4. In 80&#037; human plasma they were hydrolysed within a few minutes to metronidazole. The esters <B>3d </B>(methylpiperazinoacetate derivative)<B> </B>and <B>3f </B>were exempted since their t values were approximately 2.5 and 8.5h, respectively. A comparative pH&#150;rate profile study of N,N-diethylglycinate hydrochloride (<B>3a</B>) and 4-ethylpiperazinoacetate (<B>3e</B>) derivatives in aqueous buffer solution over the pH range 2.2&#150;10 was investigated. The results indicated that <B>3a</B> showed marked stability at pH2&#150;6 followed by accelerated hydrolysis at pH7.4. The basic ester <B>3e</B> was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters <B>3a </B>and <B>3c&#150;e</B> might be considered as good candidates for water-soluble prodrug forms of metronidazole.",
	pages = "841-848(8)",
	url = "http://www.ingentaconnect.com/content/rpsgb/jpp/2001/00000053/00000006/art00009"
	doi = "doi:10.1211/0022357011776199"
}