Modulation of membrane permeability by carbon dioxide

Promoting drug delivery across the biological membrane is a common strategy to improve bioavailability. Inspired by the observation that carbonated alcoholic beverages can increase the absorption rate of ethanol, we speculate that carbon dioxide (CO₂ ) molecules could also enhance membrane permeability to drugs. In the present work, we have investigated the effect of CO₂ on the permeability of a model membrane formed by 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipids to three drug-like molecules, namely, ethanol, 2',3'-dideoxyadenosine, and trimethoprim. The free-energy and fractional-diffusivity profiles underlying membrane translocation were obtained from μs-timescale simulations and combined in the framework of the fractional solubility-diffusion model. We find that addition of CO₂ in the lipid environment results in an increase of the membrane permeability to the three substrates. Further analysis of the permeation events reveals that CO₂ expands and loosens the membrane, which, in turn, facilitates permeation of the drug-like molecules. © 2019 Wiley Periodicals, Inc.