Abstract Purpose. A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, ...