Flunitrazepam-membrane non-specific binding and unbinding: two pathways with different energy barriers

The effect of molecular packing on flunitrazepam's ability to interact with bio-membranes was studied using dipalmitoylphosphatidylcholine monomolecular layers at the air-water interface as a model membrane. Flunitrazepam penetrated from the subphase into monolayers at lateral pressures below 44.8 mN/m and induced their concentration-dependent expansion. As inferred from the values of compressibility modulus, the elasticity of the liquid-condensed phase decreased in the presence of flunitrazepam. Although this drug hardly penetrated into high-packed monolayers, it was easily incorporated in the low-packed ones at an extent sufficient to reach the partition equilibrium. Below a molecular area of 75 A(2), contrary to what would be expected, the drug surface concentration increased as a function of surface pressure, suggesting that after its penetration in disordered phases, it became energetically or physically trapped in newly-formed liquid condensed clusters. The phenomenon of flunitrazepam penetration and release would have different energy barriers depending on the membrane phase-state.