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

Abstract

The partitioning of drugs in the phospholipid liposomeywater system has often been used as a model for the investigation of drugycell membrane interactions. Generally distributiony pH pro®les for acidic and basic compounds observed in the phospholipidywater system cannot be predicted by pro®les obtained in the octanolywater 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 coef®cients 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 signi®cant physicochemical properties and their regression coef®cients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with sizeybulk (polarizability a) 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 in¯uence 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 ®rst time that speci®c NÀH-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinonesypyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.

A New Nonlinear Equation for the Tissue/Blood Partition Coefficients of Neutral Compounds

“…The coefficients (about 0.1 and −0.6, respectively) of α and ΣCa are almost identical in all nonlinear subequations, which were used to describe compounds partitioning into lipid. In our previous work,17 we divided the compounds into neutral, cationic, and anionic compounds, and the α descriptors in different exponential term have almost identical regression coefficients, and this shows they have the same mechanism of action. In this work, these descriptors with almost identical coefficients in the same composition show that they also have the same mechanism of action in the same composition of different tissues.…”

Quantitative characterization of binding of small molecules to extracellular matrix

“…Excessive binding affinity, however, can compromise drug activity by limiting bioavailability and the local concentration around receptors. While binding to membranes is frequently characterized and correlated to properties like lipophilicity and amphiphilicity [4][5][6][7][8], nonspecific binding to ECM and other proteins, except plasma albumin and α-acid-glycoprotein [9][10][11][12], has rarely been studied. Understanding of ECM binding is important for drug disposition in tissues.…”

Screening for low aquatic bioaccumulation (1): Lipinski's ‘Rule of 5’ and molecular size

“…Most of them attempt to mimic the situation in the gastrointestinal tract to screen the absorption potential of pharmaceuticals and drug candidates. Artificial membranes have been used as more biological partition model compared with 1-octanol [46][47][48][49][50], that allow the investigation of different types of interaction with structured phospholipids related to bulk, charge state and hydrogen bonding capacity. The lipid chain ordering affects the selectivity of bilayer membranes for permeant size and shape; however, no cut-offs are feasible.…”