Contribution of ionization and lipophilicity to drug/albumin binding: a preliminary step towards biodistribution prediction

Understanding the molecular mechanisms governing albumin binding is a major challenge in absorption-distribution-metabolism-excretion prediction. To gain insight into this complex field, an ultracentrifugation method to measure the drug fraction bound to bovine serum albumin [%B(DAB)] is presented. The second part of the study shows the ependence of the experimental binding parameter on ionization and lipophilicity descriptors (pKa and log Doct 7.4 for a series of 14 structurally diverse drugs. Finally, a docking strategy is used to rationalize the findings; the results confirm the mostly nonspecific nature of the interaction of albumin with neutral ligands.