Permeability

Permeability describes the ability of a molecule to cross biological membranes such as intestinal epithelium, blood-brain barrier, or cellular membranes, representing a critical determinant of drug absorption, tissue distribution, and overall pharmacokinetic performance. High permeability supports efficient oral bioavailability and intracellular target engagement, while low permeability can limit therapeutic exposure despite strong target potency.

The pharmaceutical industry evaluates permeability early in drug discovery to predict absorption potential and guide medicinal chemistry optimisation, using in vitro models including Caco-2 cell assays and PAMPA assays. Permeability is influenced by physicochemical properties including molecular size, polarity, hydrogen bonding, lipophilicity, and ionisation state. Transporter proteins such as P-glycoprotein can further limit permeability by actively effluxing drugs, creating major challenges for central nervous system therapeutics. Formulation strategies including lipid-based delivery systems, prodrugs, and nanoparticles may enhance permeability for poorly absorbed compounds. As drug targets increasingly include intracellular proteins, nucleic acids, and central nervous system pathways, permeability remains a key optimisation parameter shaping success of both small molecules and emerging therapeutic modalities.