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

Abstract

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-B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [PorFe(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.

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

“…Since iloperidone is both a substrate and an inhibitor of CYP3A4 and CYP2D6, it seems possible that the neuroleptic can also inhibit its own metabolism. Iloperidone is also expected to moderately alter the exposure to drugs primarily cleared by CYP2C19 such as diazepam, omeprazole, mephenytoin or tricyclic antidepressants [29][30][31][32]. The magnitude of interaction may be more pronounced if alternative metabolic pathways are inhibited simultaneously.…”

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

“…Investigation of the enantioselective interaction of verapamil and amlodipine with HSA showed that ( R )-(+)-verapamil has stronger bind to HSA compared to ( S )-(-)-verapamil, while ( S )-(-)-amlodipine has a stronger bind than the ( R) -enantiomer [ 26 ]. In another study, the binding of ( S )-omeprazole (esomeprazole) and ( R )-enantiomer to HSA, under simulated physiological conditions, demonstrated that ( R )-omeprazole had higher binding constants than ( S )-omeprazole [ 27 ]. Enantioselectivity binding to HSA was also observed for xanthone derivatives [ 28 ], a promising class of compounds in medicinal chemistry [ 29 , 30 ].…”

“…Omeprazole is administrated as racemate or enantiomerically pure. However, pharmacokinetic studies suggested that the efficacy of the ( S )-omeprazole (esomeprazole) as a proton pump inhibitor compared to the ( R )-omeprazole may be dependent on the metabolic pathway [ 27 ]. Metabolism studies have demonstrated enantioselective biotransformation of ( R )-omeprazole and ( S )-omeprazole by several known enzymes belonging to the cytochrome P450 (CYP) family, such as CYP2C19, CYP2C9, CYP3A4 and CYP2D6.…”

“…CYP2C19 primarily metabolizes ( R )-omeprazole and ( S )-omeprazole by hydroxylation to hydroxyomeprazole and 5- O -desmethylomeprazole, respectively, together with other proton pump inhibitors. On the other hand, CYP3A4 metabolizes ( S )-omeprazole by oxidation to omeprazole sulfone [ 27 ]. The main metabolites of omeprazole found in plasma are hydroxyomeprazole and omeprazole sulfone.…”

“…Metabolism studies have shown that esomeprazole is metabolized to a lesser extent compared to ( R )-omeprazole by CYP2C19. The oxidation of ( S )-omeprazole by the enzyme CYP3A4 allows less excretion of omeprazole from the human body compared to the hydroxylation pathway [ 27 ]. Therefore, the ( S )-enantiomer has also been marketed as a pure enantiomer, since it has greater bioavailability compared to the racemate and because it results in less intragastric pH variability, proving its greater efficacy in the control of stomach acid secretion.…”