Drug Delivery Rule May Need Revision

Overton's rule, which pharmacologists and drug designers use to predict the transport behavior of compounds into cells, might be wrong, according to Patrick R. Unwin and colleagues at the University of Warwick, in England (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0803720105). The claim could have significant ramifications for drug design. Overton's rule states that the easier it is for a chemical to dissolve in a lipid, the more easily it will cross a cell membrane. However, using a confocal microscope and ultramicroelectrode setup, the Warwick team found that the behavior of a series of weak acids contradicts the rule. The researchers determined that carboxylic acids with longer carbon chains—and therefore greater solubility in lipids—moved more slowly across a membrane than those with shorter chains. "Our direct observations appear to totally undermine a key rule that has withstood the test of time for over a century," Unwin says. "We will now make observations with a range of other chemicals and with other techniques to further elucidate the molecular basis for our observations."