Hydroxyzine, promethazine and thioridazine interaction with phospholipid monomolecular layers at the air-water interface

In this work the interaction of Hydroxyzine, Promethazine and Thioridazine with Langmuir films of dipalmitoylphosphatidylcholine (dpPC) and dipalmitoylphosphatidic acid (dpPA), is studied. Temporal variations in lateral surface pressure (π) were measured at different initial π (π_i), subphase pH and drug-concentration. Drugs with the smallest (PRO) and largest (HYD) molecular size exhibited the lowest adsorption (ka) and the highest desorption (k_d) rate constant values, respectively. The affinity binding constants (K_b) obtained in monolayers followed the same profile (K_{b,PROb,HYDb,THI}) of the egg-PC/water partition coefficients ( P) determined in bilayers. The drug concentration required to reach the half-maximal Δπ at π_i=14 mN/m (K_0.5), was very sensitive to pH. The maximal increment in π upon drug incorporation into the monolayer (Δπ_max) will depend on the phospholipid collapse pressure (_πc), the monolayers's compressibility and drug's size, shape and charge. The higher π_c of dpPC lead to higher π_cut-off values (maximal π allowing drug penetration), if compared with dpPA. In dpPC and dpPA π_cut-off decreased as a function of the molecular size of the uncharged drugs. In dpPA, protonated drugs became electrostatically trapped at the monolayer surface hence drug penetration, monolayer deformation and π increase were impaired and the correlation between π_cut-off and drug molecular size was lost.