title: Lipophilic and polar interaction forces between acidic drugs and membrane phospholipids encoded in IAM-HPLC indexes: their role in membrane partition and relationships with BBB permeation data.
abstract: The membrane phospholipid affinity data, log k(w)(IAM), for 18 acidic and unionized drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with both log P(N) values, the n-octanol/water partition coefficients of the neutral forms, and log D(7.4) values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.4. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the "pH piston hypothesis". Since, differently from bases, electrostatic interactions between acids and phospholipids take place at the surface of phospholipid layers (choline moieties), and not near their lipophilic core (phosphate moieties), they were parameterized by a new procedure yielding "Δ'log k(w)(IAM)" parameters, i.e. the difference between the IAM retention factors observed for the analytes and those of neutral compounds with the same n-octanol partition values displayed by the analytes at pH 7.4. All acidic analytes, but one, and all unionized analytes, but the unionizable ones, showed positive Δ'log k(w)(IAM) values, indicating that they partition stronger in phospholipids than in n-octanol. Log BB values (capability to pass BBB) weakly related with both lipophilicity and phospholipid affinity values; in contrast they are inversely related with Δ'log k(w)(IAM) values. The relationships between log BB and Δ'log k(w)(IAM) practically overlapped the previously found log BB/Δlog k(w)(IAM) relationships for bases. The excess of polar interaction component between acidic drugs and phospholipids, mainly electrostatic forces, although enhancing partition in phospholipids, hinders membrane passage, analogously to the behavior previously reported for bases. The study suggests that IAM-HPLC is an effective technique to perform simple and fast measurements of the intermolecular recognition forces related to membrane partition and permeation. This can contribute to better understand the mechanisms governing both partition of charged species in cell membranes and passage through them, also allowing the possible optimization of the pharmacokinetic properties of the drugs at the early stages of their development.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Grumetto
authors.forename: Carmen
authors.initials: C
authors.lastname: Carpentiero
authors.forename: Paola
authors.initials: P
authors.lastname: Di Vaio
authors.forename: Francesco
authors.initials: F
authors.lastname: Frecentese
authors.forename: Francesco
authors.initials: F
authors.lastname: Barbato
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015507:Drugs, Investigational / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008567:Membranes, Artificial; D008954:Models, Biological; D010539:Permeability; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism
chemical_list: D015507:Drugs, Investigational; D008567:Membranes, Artificial; D010743:Phospholipids