pH‐Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure‐Activity Relationship Analysis

The partitioning of drugs in the phospholipid liposome/water system has often been used as a model for the investigation of drug/cell membrane interactions. Generally distribution/pH profiles for acidic and basic compounds observed in the phospholipid/water system cannot be predicted by profiles obtained in the octanol/water system. This is true especially for pH regions where acids and bases are ionized. Based on the well-known pH-partition theory our nonlinear regression analysis of published pH-dependent liposome-water distribution coefficients of 18 basic and acidic drugs resulted in equations with satisfactory predictive power. Surprisingly the separate equations describing the partitioning of neutral, anionic or cationic drugs into phosphatidylcholine liposomes are rather similar with respect to significant physicochemical properties and their regression coefficients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with size/bulk (polarizability α) and decreases with polarity characterized by the sum of substructural partial charges. Furthermore, for the neutral compounds and their cations an unfavorable effect of H-bond acceptor strength on distribution is found. Unexpectedly the H-bond donor effect of neutral or ionized species does not seem to influence their liposome partitioning behavior (as observed within each group of neutral, cationic or anionic drugs). Generally the distribution of ionizable molecules into phospholipid bilayers decreases with increasing degree of ionization. In this data set it was found for the first time that specific N-H-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinones/pyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.