Synthesis and evaluation of mutual prodrugs of isoniazid, p-amino salicylic acid and ethambutol

Ethambutol (EB), isoniazid (INH) and p-amino salicylic acid (PAS) are potent antitubercular agents having various side effects due to formation of toxic metabolites.The present study aims towards prevention of these side effects through mutual prodrug formation.Mutual prodrugs of EB with PAS (PE), PAS with PAS (PP) and INH with PAS (PI) were synthesized and characterized.Hydrolytic and absorption studies were performed in SGF (synthetic gastric fluid) and SIF (synthetic intestinal fluid).In vivo studies were also performed to confirm the release profile of the synthesized prodrugs.Formation of imide and ester functionalities was confirmed by IR spectra.In vitro hydrolysis studies in SGF and SIF reveal that these mutual prodrug conjugates do not hydrolyze appreciably and are absorbed unhydrolyzed.In vivo studies showed greater serum concentrations of EB, PAS and INH than their concentrations when given alone and isoniazid concentrations were greater except for PP.Peak plasma levels were attained after 3 h but these levels were reduced 0.6 times.Thus, mutual prodrugs PI and PE significantly eliminate the problem of fast metabolism, toxicity and local irritation and reduction of therapeutic doses.In the case of PP only local irritation could be avoided.