Overton Overturned

A century-old rule used throughout the pharma industry may have been overturned by new research in the UK. Researchers at the University of Warwick have demonstrated that drug transport rates across cell membranes may be hundreds of times slower than are predicted by Overton’s Rule, which could have serious implications for developing and testing new drugs.

Put simply, Overton’s Rule says that the more lipophilic a compound is, the faster it will enter a cell. The Rule was first outlined in the 1890s by Ernst Overton of the University of Z├╝rich. He quantified the rule to allow biochemists and others to predict how fast the membrane crossing would take place. One of the key parameters in his equation is K, lipophilicity. Bigger K, faster transport.

For over a century, medicinal chemists have used this relationship to shape their studies and clinical trials.

Now, a confocal microscopy study used in conjunction with an ultramicroelectrode led by Patrick Unwin has allowed the team to follow every step of the membrane-crossing process. The results are stunning. While the test compounds (acids) did diffuse across a lipid membrane, they did so at rates that were diametrically opposed to those prediction by Overton’s Rule. The researchers studied four acids (acetic, butanoic, valeric, and hexanoic) that had increasingly larger “acyl” (or carbon) chains. The longer the carbon chain, the easier the chemical dissolves in lipids and, therefore, according to Overton, the faster they should diffuse across a lipid membrane.

The Warwick work showed instead that the most lipophilic molecules were actually transported the slowest.

REFERENCE: Proc Natl Acad Sci: Quantitative visualization of passive transport across bilayer lipid membranes