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    Interface-Mediated Mechanism of Action-The Root of the Cytoprotective Effect of Immediate-Release Omeprazole

    Year: 2021

    Journal: J. Med. Chem., Volume 64, APR 22, page 5171–5184

    Authors: Lopes-de-Campos, Daniela; Pereira-Leite, Catarina; Fontaine, Philippe; Coutinho, Ana; Prieto, Manuel; Sarmento, Bruno; Jakobtorweihen, Sven; Nunes, Claudia; Reis, Salette

    Organizations: Fundacao para a Ciencia e Tecnologia (FCT) [PD/BD/105957/2014, IF/00293/2015]; FCT; Programa Operacional Capital Humano (POCH); BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences); [NORTE-01-0145-FEDER-000012]; [UIDB/04565/2020]

    Omeprazole is usually administered under an enteric coating. However, there is a Food and Drug Administration-approved strategy that enables its release in the stomach. When locally absorbed, omeprazole shows a higher efficacy and a cytoprotective effect, whose mechanism was still unknown. Therefore, we aimed to assess the effect of the absorption route on the gastric mucosa. 2D and 3D models of dipalmitoylphos-phatidylcholine (DPPC) at different pH values (5.0 and 7.4) were used to mimic different absorption conditions. Several experimental techniques, namely, fluorescence studies, X-ray scattering methodologies, and Langmuir monolayers coupled with microscopy, X-ray diffraction, and infrared spectroscopy techniques, were combined with molecular dynamics simulations. The results showed that electrostatic and hydrophobic interactions between omeprazole and DPPC rearranged the conformational state of DPPC. Omeprazole intercalates among DPPC molecules, promoting domain formation with untilted phospholipids. Hence, the local release of omeprazole enables its action as a phospholipid-like drug, which can reinforce and protect the gastric mucosa.
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