Microcavity-Supported Lipid Bilayers; Evaluation of Drug-Lipid Membrane Interactions by Electrochemical Impedance and Fluorescence Correlation Spectroscopy.

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) platforms 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 drug-membrane interactions across seven drugs from different classes, including nonsteroidal anti-inflammatories: 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 1,2-dioleyl- sn-glycerophosphocholine and binary bilayers over physiologically relevant drug concentrations. Although 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 4 mM. Conversely, Dic and Rif dramatically altered bilayer fluidity, suggesting their translocation through the bilayer, and EIS data showed that 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.

Upper gastrointestinal tract transit times of tablet and drinkable solution formulations of alendronate: a bioequivalence and a quantitative, randomized study using video deglutition.

The bioequivalence and upper digestive tract transit time of a drinkable solution of 70 mg/100 mL alendronate was compared to reference tablets. A randomized, single- dose, two-way crossover study of the rate of urinary recovery of alendronate during 36 h (AE((0-36 h))) by HPLC, in 104 healthy young male volunteers, showed that AE((0-36 h)) and the maximum excretion rate (R (max)) were within the accepted range of bioequivalence 81.8-105.7 and 81.7-106.2, respectively. To characterize the oesophageal passage time of the two alendronate formulations, we performed a randomized, controlled study, in 24 healthy men and women (mean 52 years old), who took the formulations standing or lying down, by an X-ray video deglutition system. When taken in the standing position, both formulations had equal mean transit times from mouth to stomach and tablet disintegration but data dispersion was significantly smaller with the liquid form. When taken in lying position, drinkable alendronate had shorter and less variable median transit times compared to the tablets. These results show that the drinkable alendronate formulation is bioequivalent to the tablets and may be advantageous in patients in whom the transit or disintegration of the tablets is impaired.