Anna Galkin1, Adyary Fallarero, Pia M Vuorela. 1. Drug Discovery and Development Technology Center (DDTC), Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Abstract
OBJECTIVES: The presence of coumarins in human diet, their multiple pharmacological properties and occurrence in various herbal remedies represent significant reasons to explore their membrane permeability, as a first event contributing to coumarins oral bioavailability. Thus, we evaluated the permeability and cytotoxicity of 18 coumarins, with different substitution patterns involving OH, OCH3 and CH3 groups. METHODS: A modified Caco-2 permeability model was used, in which the permeability test is performed with a robotic workstation and cells are grown on 96-well plates for 7 days. KEY FINDINGS: All studied coumarins were highly permeable, with calculated Papp values that varied within 4.1 x 10(-5) to 2.1 x 10(-4) in apical to basolateral studies and within 1.8 x 10(-5) to 7.0 x 10(-5) in basolateral to apical studies. The efflux ratio remained in all cases below 1. It was demonstrated that the type and position of substituents contributed more to the permeability than the number of substituents. CONCLUSIONS: The results allowed us to predict that these coumarins are well absorbed in the gut lumen and efflux is not limiting the absorption. Five coumarins had an influence on the mitochondrial function of Caco-2 cells (1 < 80%, 4 > 120%), according to the WST-1 cytotoxicity test, but this does not seem to affect the permeability of the compounds.
OBJECTIVES: The presence of coumarins in human diet, their multiple pharmacological properties and occurrence in various herbal remedies represent significant reasons to explore their membrane permeability, as a first event contributing to coumarins oral bioavailability. Thus, we evaluated the permeability and cytotoxicity of 18 coumarins, with different substitution patterns involving OH, OCH3 and CH3 groups. METHODS: A modified Caco-2 permeability model was used, in which the permeability test is performed with a robotic workstation and cells are grown on 96-well plates for 7 days. KEY FINDINGS: All studied coumarins were highly permeable, with calculated Papp values that varied within 4.1 x 10(-5) to 2.1 x 10(-4) in apical to basolateral studies and within 1.8 x 10(-5) to 7.0 x 10(-5) in basolateral to apical studies. The efflux ratio remained in all cases below 1. It was demonstrated that the type and position of substituents contributed more to the permeability than the number of substituents. CONCLUSIONS: The results allowed us to predict that these coumarins are well absorbed in the gut lumen and efflux is not limiting the absorption. Five coumarins had an influence on the mitochondrial function of Caco-2 cells (1 < 80%, 4 > 120%), according to the WST-1 cytotoxicity test, but this does not seem to affect the permeability of the compounds.
Authors: Sebastian F Beyer; Alexander Beesley; Philipp F W Rohmann; Holger Schultheiss; Uwe Conrath; Caspar J G Langenbach Journal: Plant J Date: 2019-07-01 Impact factor: 6.417