Biological and metabolic study of naproxen-propyphenazone mutual prodrug.

Naproxen-propyphenazone (NAP-PP) esters were synthesized as prodrugs with the aim of improving the therapeutic index through prevention of gastrointestinal irritation and bleeding. The structures of the synthesized NAP-PP hybrid esters were confirmed by IR and 1H NMR spectroscopy and their purity was established by elemental analysis, HPLC and TLC. The release of NAP as well as PP derivatives, from the ester prodrugs was studied. A validated analytical HPLC method for the estimation of the NAP, and the prodrugs was developed. Also the enzymatic hydrolysis products of the ester were identified by GC-MS and in conjugation with HPLC. The kinetics of ester hydrolysis was studied in two different non-enzymatic buffer solutions, at pH 1.2, and 7.4 as well as in liver homogenates. Study of analgesic and anti-inflammatory properties in comparison with the reference compounds has shown that both analgesic and anti-inflammatory activities were present at the same doses of the investigated compounds. The ester III was found to be less irritating to gastric mucosal membrane than the parent drugs. These results suggest that the synthesized prodrugs are characterized by better therapeutic index than the parent drugs.