Membrane Interaction of Ibuprofen with Cholesterol-Containing Lipid Membranes

Abstract

Deciphering the membrane interaction of drug molecules is important for improving drug delivery, cellular uptake, and the understanding of side effects of a given drug molecule. For the anti-inflammatory drug ibuprofen, several studies reported contradictory results regarding the impact of ibuprofen on cholesterol-containing lipid membranes. Here, we investigated membrane localization and orientation as well as the influence of ibuprofen on membrane properties in POPC/cholesterol bilayers using solid-state NMR spectroscopy and other biophysical assays. The presence of ibuprofen disturbs the molecular order of phospholipids as shown by alterations of the 2H and 31P-NMR spectra of the lipids, but does not lead to an increased membrane permeability or changes of the phase state of the bilayer. 1H MAS NOESY NMR results demonstrate that ibuprofen adopts a mean position in the upper chain/glycerol region of the POPC membrane, oriented with its polar carbonyl group towards the aqueous phase. This membrane position is only marginally altered in the presence of cholesterol. A previously reported result that ibuprofen is expelled from the membrane interface in cholesterol-containing DMPC bilayers could not be confirmed.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Ketoprofen [261][262][263][264], Aspirin [199,229,261,[265][266][267][268][269][270][271], Piroxicam [185,261], Ibuprofen [132,166,199,203,265,270,[272][273][274][275][276][277], Indomethacin [277], Diclofenac [132,270], Xanthone derivatives (KS1, KS2, KS3) [278], Indomethacin [279], Carane derivatives [147],…”

Synthesis of Spin-Labeled Ibuprofen and Its Interaction with Lipid Membranes

“…In this regard, new data on the processes of interaction of ibuprofen with lipid membranes and with proteins, previously inaccessible for detection and description, could be extremely useful. Different methods, such as X-ray diffraction/scattering [17,18], differential scanning calorimetry [19], quasielastic neutron scattering [20], fluorescence [21], neutron spin echo [22], electrochemical impedance [23], Raman microspectroscopy [24], vibrational sum frequency spectroscopy [25], powder NMR [26] and electron paramagnetic resonance (EPR) spectroscopy [27,28] are used to study ibuprofen-mediated changes in model lipid membranes.…”

Ibuprofen and the Phosphatidylcholine Bilayer: Membrane Water Permeability in the Presence and Absence of Cholesterol

“…For example, an X-ray scattering and electron density study on a DMPC bilayer containing 20 mol % of cholesterol shows that ibuprofen is expelled from the tail groups (which is a preferred position of ibuprofen in the absence of cholesterol) and partitioned in the head groups . However, a recent study on the effect of ibuprofen on POPC/cholesterol bilayers using solid-state NMR spectroscopy and other biophysical assays reported that ibuprofen disturbs the molecular order of liquid crystalline phospholipid membranes and that the presence of cholesterol in membranes has only a very small effect on the localization of ibuprofen in the model membrane . MD studies of DMPC-based bilayers by Khajeh et al show that ibuprofen prefers to be located in the hydrophobic acyl chain region of DMPC/cholesterol bilayers and causes the ordering of hydrocarbon tails when cholesterol is less than 25 mol %, but when more than 50 mol % cholesterol is present, ibuprofen perturbs and disorders the flexible chains of DMPC and reduces the acyl chain order parameter .…”

“…However, the detailed mechanism of action by which cholesterol may influence the drug behavior has not been fully explored . The differential effect of ibuprofen on the lipid bilayer, including cholesterol-containing bilayers, has been previously reported but includes contradictions and thus still requires further elaboration. ,,, …”