SCAN: In vitro models for intestinal absorption: application to pharmacologically active flavonoids

Abstract:
In vitro models are becoming more popular for prediction of drug metabolism and bioavailability. These models are more prone to automation and high throughput screening, but also allow reduction of the use of animals in preliminary tests where usually most compounds are discarded. Being less complex systems they are easier to interpret and correlate with in vivo observations. Among the in vitro systems used for the study of drug absorption there are two models which are the most used: Caco-2 and PAMPA (parallel artificial membrane permeability assay). In the Caco-2 model, permeability is tested across a differentiated monolayer of cells of the human colon adenocarcinoma, while in the PAMPA method an artificial phospholipidic membrane is used with the same purpose.

Flavonoids are a large group of compounds naturally occurring in several plants and fruits, as glycosides or, less frequently, as their aglycones. Their abundance in human diet and their role in the prevention of cancer and cardiovascular diseases has attracted substantial attention. However, despite all the evidence of biological activity, there is limited acceptance of some of these compounds as valuable therapeutic agents which is mostly related to their physical-chemical properties and pre-systemic metabolism, which may significantly affect the therapeutic outcome due to bioavailability issues. Some of these compounds have to be metabolized prior to absorption but this may be hampered due to their low solubility. Solubility issues may usually be tackled by the preparation of suitable formulations containing solubilization aids, however for particularly difficult compounds the preparation of a prodrug may be necessary.

The work presented in this seminar refers to the application of in vitro models to the study of the intestinal absorption and the metabolism of the pharmacologically active flavonoids diosmin, hesperidin, naringin and their correspondent aglycones. The same studies were carried on soluble phosphate derivatives of the glycosilated flavonoids, prepared with the objective of increasing the availability for metabolism by gycosidases produced by intestinal microflora and consequently, increase intestinal absorption.