jp7b08359_si_001.pdf (2.03 MB)
Thermodynamics of Indomethacin Adsorption to Phospholipid Membranes
journal contribution
posted on 2017-10-24, 00:00 authored by Amanda
D. Fearon, Grace Y. StokesUsing second-harmonic generation,
we directly monitored adsorption
of indomethacin, a nonsteroidal anti-inflammatory drug, to supported
lipid bilayers composed of phospholipids of varying phase, cholesterol
content, and head group charge without the use of extrinsic labels
at therapeutically relevant aqueous concentrations. Indomethacin adsorbed
to gel-phase lipids with a high binding affinity, suggesting that
like other arylacetic acid-containing drugs, it preferentially interacts
with ordered lipid domains. We discovered that adsorption of indomethacin
to gel-phase phospholipids was endothermic and entropically driven,
whereas adsorption to fluid-phase phospholipids was exothermic and
enthalpically driven. As temperature increased from 19 to 34 °C,
binding affinities to gel-phase lipids increased by 7-fold but relative
surface concentration decreased to one-fifth of the original value.
We also compared our results to the entropies reported for indomethacin
adsorbed to surfactant micelles, which are used in drug delivery systems,
and assert that adsorbed water molecules in the phospholipid bilayer
may be buried deeper into the acyl chains and less accessible for
disruption. The thermodynamic studies reported here provide mechanistic
insight into indomethacin interactions with mammalian plasma membranes
in the gastrointestinal tract and inform studies of drug delivery,
where indomethacin is commonly used as a prototypical, hydrophobic
small-molecule drug.