Many drugs have intracellular or membrane-associated targets thus understanding their interaction with
the cell membrane is of value in drug development. Cell-free tools used to predict membrane interactions
should replicate the molecular organization of the membrane. Microcavity array supported lipid bilayer
(MSLB) platform are versatile biophysical models of the cell membrane that combine liposome-like
membrane fluidity with stability and addressability. We used an MSLB herein to interrogate drugmembrane interactions across seven drugs from different classes, including non-steroidal antiinflammatories; Ibuprofen (Ibu) and Diclofenac (Dic), antibiotics; Rifampicin (Rif), Levofloxacin (Levo)
and Pefloxacin (Pef), and bisphosphonates; Alendronate (Ale) and Clodronate (Clo). Fluorescence
lifetime correlation spectroscopy (FLCS) and electrochemical impedance spectroscopy (EIS) were used to
evaluate the impact of drug on DOPC and binary bilayers over physiologically relevant drug
concentrations. Whereas FLCS data revealed Ibu, Levo, Pef, Ale and Clo had no impact on lipid lateral
mobility, EIS which is more sensitive to membrane structural change, indicated modest but significant
decreases to membrane resistivity consistent with adsorption but weak penetration of drugs at the
membrane. Ale and Clo, evaluated at pH 5.25, did not impact the impedance of the membrane except at
concentrations exceeding 4mM. Conversely, Dic and Rif dramatically altered bilayer fluidity, suggesting
their translocation through the bilayer and, EIS data, showed resistivity of the membrane decreased
substantially with increasing drug concentration. Capacitance changes to the bilayer in most cases were
insignificant. Using a Langmuir-Freundlich model to fit the EIS data, we propose Rsat as an empirical
value that reflects permeation. Overall, the data indicate that Ibu, Levo, and Pef, adsorb at the interface of
the lipid membrane but Dic and Rif interact strongly, permeating the membrane core modifying the
water/ion permeability of the bilayer structure. These observations are discussed in the context of
previously reported data on drug permeability and Log P.