Total drug's last stand on phospholipidosis: Unbound drug rules!

The unbound (free) drug hypothesis is now correctly termed the unbound drug principle. Despite it offering a basic and simple mechanism for the action of drugs both in vitro and in vivo, there are still misconceptions. The literature provides a challenge to the unbound drug principle in addressing the common preclinical finding of phospholipidosis associated with basic compounds. Similar agents (differentiated mainly by pKa) with identical unbound plasma concentrations, in vivo, can show very different effects. In this commentary we explain how this finding is in keeping with unbound drug principles, as the change in pKa inversely correlates to Kd and enhanced affinity for phospholipid. The majority of a basic drug, associated with tissue, is reversibly bound to abundant acidic phospholipid rather than interstitial and cytosolic proteins. Total tissue concentrations may therefore correlate with phospholipidosis better than unbound plasma drug concentrations, however, once phospholipid Kd is considered the correlation becomes obvious. In the specific case of phospholipidosis, measurement of tissue concentrations for basic drugs provides a direct measure of target occupancy. SIGNIFICANCE STATEMENT: The importance of this commentary is to address what may be seen as an exception to the unbound (free) drug principle and has been quoted as such. By explaining the role of unbound drug and target (phospholipid) affinity the anomaly is clarified. Moreover, the total tissue concentrations in phospholipidosis are rationalized as actually a measure of target occupancy, acidic phospholipids.