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

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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 SMD water -B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [Por •+ Fe IV (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.