Intestinal absorption of S-nitrosothiols: Permeability and transport mechanisms

• Published in: Biochemical pharmacology 2018-09, Vol.155, p.21-31
• Main Authors: Bonetti, Justine, Zhou, Yi, Parent, Marianne, Clarot, Igor, Yu, Haiyan, Fries-Raeth, Isabelle, Leroy, Pierre, Lartaud, Isabelle, Gaucher, Caroline
• Format: Article
• Language: English
• Subjects: Biochemistry; Biochemistry, Molecular Biology; Biological Transport - drug effects; Biological Transport - physiology; Caco-2 Cells; Cell Behavior; Cell Membrane Permeability - drug effects; Cell Membrane Permeability - physiology; Cell Survival - drug effects; Cell Survival - physiology; Cellular Biology; Galenic pharmacology; Humans; Intestinal Absorption - drug effects; Intestinal Absorption - physiology; Intestinal permeability; Life Sciences; Medication; Nitric oxide; Passive diffusion; Pharmaceutical sciences; Pharmacology; S-Nitrosothiols; S-Nitrosothiols - metabolism; S-Nitrosothiols - pharmacology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.06.018

[Display omitted] S-Nitrosothiols, a class of NO donors, demonstrate potential benefits for cardiovascular diseases. Drugs for such chronic diseases require long term administration preferentially through the oral route. However, the absorption of S-nitrosothiols by the intestine, which is the first limiting barrier for their vascular bioavailability, is rarely evaluated. Using an in vitro model of intestinal barrier, based on human cells, the present work aimed at elucidating the mechanisms of intestinal transport (passive or active, paracellular or transcellular pathway) and at predicting the absorption site of three S-nitrosothiols: S-nitrosoglutathione (GSNO), S-nitroso-N-acetyl-l-cysteine (NACNO) and S-nitroso-N-acetyl-d-penicillamine (SNAP). These S-nitrosothiols include different skeletons carrying the nitroso group, which confer different physico-chemical characteristics and biological activities (antioxidant and anti-inflammatory). According to the values of apparent permeability coefficient, the three S-nitrosothiols belong to the medium class of permeability. The evaluation of the bidirectional apparent permeability demonstrated a passive diffusion of the three S-nitrosothiols. GSNO and NACNO preferentially cross the intestinal barrier though the transcellular pathway, while SNAP followed both the trans- and paracellular pathways. Finally, the permeability of NACNO was favoured at pH 6.4, which is close to the pH of the jejunal part of the intestine. Through this study, we determined the absorption mechanisms of S-nitrosothiols and postulated that they can be administrated through the oral route.