Novel approach to enhance oral bioavailability of drugs with poor permeability

Abstract

T epithelial enterocyte barrier of the gastrointestinal (GI) tract limits the absorption of many oral drugs to the systemic circulation. Modulation of intercellular tight junctions has long been considered a potential tool to enhance drug delivery across these biological barriers. However, early modulators (e.g., Ca2+ chelators, surfactants, modified fatty acids and esters, and polymers) had unspecific modes of action and insufficient separation between efficacy and toxicity, precluding their clinical use. Recent knowledge regarding the molecular composition and mechanisms regulating tight junctions and adherens junctions has led to a new generation of intercellular junction modulators based on junction protein/peptide mimetics and relevant signaling pathways. E-cadherin peptides (ECPs) represent a class of these new modulators and have shown promise in enhancing small molecule drug delivery across the blood-brain barrier via reversible modulation. Here, the potential of ECPs to enhance oral bioavailability of small molecule drugs that have limited gut absorption was investigated. In vitro permeability and in vivo pharmacokinetic studies have been performed to demonstrate the feasibility of the ECP-based oral drug delivery approach. Results showed that ECPs substantially increased the permeability of the model drugs, as well as their systemic exposure after oral administration. In conclusion, ECPs-based formulations should be further developed as a vehicle to enhance oral bioavailability of poorly permeable drugs.