Titre du document / Document title

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

Auteur(s) / Author(s)

MAHFOUZ Nadia M. ⁽¹⁾ ; HASSAN Maha A. ⁽²⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, EGYPTE
⁽²⁾ Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, EGYPTE

Résumé / Abstract

A series of amino acid esters (3a-e) 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 (3a) and 4-ethylpiperazinoacetate (3e) 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 (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80 % human plasma at 37°C. In all casesthe 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, t1/2, 4-16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutes to metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t1/2 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethyl-piperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2-10 was investigated. The results indicated that 3a showed marked stability at pH 2-6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e 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 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.

Revue / Journal Title

Journal of pharmacy and pharmacology   ISSN 0022-3573   CODEN JPPMAB 

Source / Source

2001, vol. 53, n^o6, pp. 841-848 (11 ref.)

Langue / Language

Anglais

Editeur / Publisher

Pharmaceutical Press, Wallingford, ROYAUME-UNI  (1949) (Revue)

Mots-clés anglais / English Keywords

Metronidazole ; Antifungal agent ; Prodrug ; Ester ; Chemical synthesis ; Hydrolysis ; Bioavailability ; Solubility ; Lipophily ; Physicochemical properties ; Stability ; In vitro ; Intravenous administration ; Rabbit ; Animal ; Blood plasma ; Imidazole derivatives ; Nitro compound ; Absorption ; Pharmacokinetics ; Lagomorpha ; Mammalia ; Vertebrata ;

Mots-clés français / French Keywords

Métronidazole ; Antifongique ; Promédicament ; Ester ; Synthèse chimique ; Hydrolyse ; Biodisponibilité ; Solubilité ; Lipophilie ; Propriété physicochimique ; Stabilité ; In vitro ; Voie intraveineuse ; Lapin ; Animal ; Plasma sanguin ; Imidazole dérivé ; Composé nitro ; Absorption ; Pharmacocinétique ; Lagomorpha ; Mammalia ; Vertebrata ;

Mots-clés espagnols / Spanish Keywords

Metronidazol ; Antifúngico ; Promedicamento ; Ester ; Síntesis química ; Hidrólisis ; Biodisponibilidad ; Solubilidad ; Lipofilia ; Propiedad fisicoquímica ; Estabilidad ; In vitro ; Vía intravenosa ; Conejo ; Animal ; Plasma sanguíneo ; Imidazol derivado ; Compuesto nitro ; Absorción ; Farmacocinética ; Lagomorpha ; Mammalia ; Vertebrata ;

Localisation / Location

INIST-CNRS, Cote INIST : 984, 35400009774515.0090