Stereoselective Metabolism of Omeprazole by Cytochrome P450 2C19 and 3A4: Mechanistic Insights from DFT Study.

The efficacy of S-omeprazole as a proton pump inhibitor compared with that of its enantiomer R-omeprazole is studied using density functional theoretical calculations. The pharmacokinetic studies suggest that the efficacy of S-omeprazole presumably depends on metabolic pathway and excretion from the human body. The density functional theory calculations at SMDwater-B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [Por•+FeIV(SH)O], of CYP2C19 enzyme with high-spin quartet and low-spin doublet states demonstrate C-H bond activation mechanism through a two-state rebound process for the hydroxylation of R-omeprazole and S-omeprazole. The calculated activation free energy barriers for the hydrogen abstraction are 15.7 and 17.5 kcal/mol for R-omeprazole and S-omeprazole, respectively. The hydroxylation of R-omeprazole and S-omeprazole is thermodynamically favored; however, the hydroxylated intermediate of S-omeprazole further disintegrates to metabolite 5- O-desmethylomeprazole with a higher kinetic barrier. We have examined the sulfoxidation of S-omeprazole to omeprazole sulfone metabolite by CYP3A4, and the observed activation free energy barrier is 9.9 kcal/mol. The computational results reveal that CYP2C19 exclusively metabolizes R-omeprazole to hydroxyomeprazole, which is hydrophilic and can easily excrete, whereas CYP3A4 metabolizes S-omeprazole to lipophilic sulfone; hence, the excretion of this metabolite would be relatively slower from the body. The spin density analysis and molecular orbital analysis performed using biorthogonalization calculations indicate that R-omeprazole favors high-spin pathway for metabolism process whereas S-omeprazole prefers the low-spin pathway.