Design, synthesis, hydrolysis kinetics and phamacodynamic profiles of histidine and alanine conjugates of aceclofenac.
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.
Department of Pharmaceutical Chemistry, Sree Vidyanikethan College of Pharmacy, Sree Sainath Nagar, Tirupati, Andhra, Pradesh-517102, India. arunrasheed@rediffmail.com
Arun
A
Rasheed
C K Ashok
CK
Kumar
D000409:Alanine / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D006639:Histidine / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
D004008:Diclofenac; D006639:Histidine; D000409:Alanine; C056498:aceclofenac