Localization of flunitrazepam in artificial membranes. A spectrophotometric study about the effect the polarity of the medium exerts on flunitrazepam acid-base equilibrium

Abstract

In the present paper we tried to test the hypothesis that nonspecific flunitrazepam–membrane interactions are consistent with drug molecules accommodated between lipid molecules, becoming an integral part of the bilayer. We developed a spectrophotometric method to determine FNTZH⁺ equilibrium dissociation constant and applied it to the study of the acid-base equilibria of this drug in homogeneous media of different polarity. In these conditions, pK decreased with the decrement in the dielectric constant (D) of the media. These results, analyzed under the light of the theory developed by Fernandez and Fromherz (1977; J. Phys. Chem. 81, 1755–1761) let us infer that flunitrazepam is localized a region with D=60. This D value is lower that D_water=78 and higher than D of hydrocarbon chains zone (D=2–5) and would correspond to D of the region of polar groups. This result is compatible with the hypothesis.