Design, synthesis, hydrolysis kinetics and phamacodynamic profiles of histidine and alanine conjugates of aceclofenac

Dizajniranje, sinteza, kinetika hidrolize i farmakodinamski profili konjugata aceklofenaka s histidinom i alaninom

Croatian Pharmaceutical Society 2010

The gastrointestinal toxicity associated with aceclofenac can be reduced by condensing its carboxylic acid group with methyl esters of amino acids like histidine and alanine to give amide linkage by the Schotten-Baumann method. Physicochemical characterization of the conjugates was carried out by various analytical and spectral methods. The synthesized conjugates were also subjected to in vitro hydrolysis in simulated gastric fluid (SGF) at pH 1.2, simulated intestinal fluid (SIF) at pH 7.4 and SIF + 80 % human plasma at pH 7.4. The release of free aceclofenac from histidine and alanine conjugated aceclofenac showed negligible hydrolysis in SGF compared to SIF. This indicated that the conjugates do not break in stomach, but release aceclofenac in SIF. Both synthesized conjugates showed excellent pharmacological response and encouraging hydrolysis rate in SIF and SIF + 80 % human plasma. Marked reduction of the ulcer index and comparable increase in analgesic and anti-inflammatory activities were obtained in both cases compared to aceclofenac alone. These findings suggest that the conjugates are better in action compared to the parent drug and have fewer gastrointestinal side-effects.
Gastrointestinalna toksičnost aceklofenaka može se umanjiti kondenzacijom karboksilne skupine aceklofenaka s metilnim esterima aminokiselina poput histidina i alanina, pri čemu se stvaraju nove amidne veze po Schotten-Baumannovoj metodi. Fizikokemijska karakterizacija konjugata provedena je različitim analitičkim i spektralnim metodama. Nadalje, praćena je hidroliza sintetiziranih konjugata in vitro u simuliranoj gastričnoj tekućini (SGF) pri pH 1,2, simuliranoj intestinalnoj tekućini (SIF) pri pH 7,4 i simuliranoj intestinalnoj tekućini s 80 % humane plazme pri pH 7,4. Oslobađanje aceklofenaka iz konjugata s histidinom, odnosno alaninom, bilo je zanemarivo u SGF-u, u odnosu na oslobađanje u SIF-u. To ukazuje da su konjugati stabilni u želucu, dok se u SIF-u iz njih oslobađa aceklofenak. Oba konjugata daju izvrstan farmakološki odgovor i zadovoljavajući stupanj hidrolize u SIF-u i smjesi SIF-a i humane plazme. Oba konjugata pokazala su značajno smanjenu ulcerogenost i pojačano analgetsko i protuupalno djelovanje u odnosu na aceklofenak. Rezultati ukazuju na prednost konjugata u odnosu na samu ljekovitu tvar.

NSAID; aceclofenac; amino acid conjugate; mutual prodrugs; pharmacokinetics; ulcerogenicity; aceklofenak; aminokiselinski konjugat; prolijekovi; farmakokinetika; ulcerogenost; text; info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion

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