Drug-drug interaction studies are essential building blocks in drug development. Thiazolidinediones (TZDs: pioglitazone, and rosiglitazone) are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, which have been widely used in the treatment of type 2 diabetes as insulin sensitizers. Esomeprazole, the (S) -isomer of omeprazole, is the first proton pump inhibitor (PPI) developed as a single isomer for the treatment of acid-peptic disease by specific inhibition of H+K+- ATPase in gastric parietal cells. The role of esomeprazole on the pharmacodynamic activity of TZDs is not currently known; however, there is the possibility of drug interaction (DI) leading to decreased activity of TZDs. The study was planned to investigate the safety and effectiveness of TZDs therapy in the presence of esomeprazole in animal models.