In this study, three sulfonamide prodrugs of metformin were designed and synthesized. The bioconversion of the sulfonamide prodrugs by glutathione-S-transferase (GST) was evaluated in rat and human liver S9 fractions as well as with recombinant human GST forms. One of the prodrugs (3) was bioactivated by GST and released metformin in a quantitative manner, whereas the two others were enzymatically stable. Prodrug 3 had a much higher logD value relative to metformin and it was reasonably stable in both acidic buffer and rat small intestine homogenate, which indicates that this prodrug has the potential to increase the oral absorption of metformin.