Lv_2025_Int.J.Biol.Macromol_311_143967

Carboxylesterases serve as principal Phase I metabolic enzymes that critically regulate the metabolism, efficacy, and safety profiles of ester-based pharmaceuticals in humans. This study investigated 23 clinically relevant cardiovascular agents to assess their inhibitory potential against human carboxylesterase isoforms hCES1A and hCES2A. The findings demonstrated that hypolipidemic agents simvastatin (C-16) and lovastatin (C-17), along with antithrombotic compounds prasugrel (C-22) and clopidogrel (C-23), exhibited potent inhibition against hCES1A, with the lowest IC(50) value observed at 0.48 microM. These four therapeutic agents combined with ezetimibe (C-18) demonstrated concurrent inhibition of hCES2A, exhibiting the lowest observed IC(50) value of 0.55 microM. Selectivity profiling demonstrated that C-16, C-17, C-22 and C-23 exhibited preferential inhibition against hCES1A/hCES2A compared with three other serine hydrolases, whereas C-18 specifically targeted hCES2A. Further research has found that these five drugs can inhibit hCES2A-mediated CPT-11 hydrolytic metabolism. Kinetic characterization delineated the inhibition modality exerted by the test compounds on hCES1A/hCES2A-mediated hydrolytic activity towards NLMe/FD. Molecular docking analysis elucidated the reason why these drugs (C-16/18 and C-22/23) did not exhibit competitive inhibition behavior in hCES2A inhibition experiments. In addition, the five drugs demonstrated significant inhibition of hCES2A activity in Caco2 cells, exhibiting clear concentration dependence. These drugs represent potent inhibitors of carboxylesterases, providing valuable insights into clinical medication.