Researchers find conventional rule for calculating drug transport rates is wrong

A new study by research chemists at the University of Warwick has challenged a century old rule of pharmacology that defined how quickly key chemicals can pass across cell walls.

The new observations suggest that the real transport rates could be a hundred times slower than predicted by the century old "Overton's Rule". This could have major implications for the development and testing of many future drugs.

Overton's rule says that the easier it is for a chemical to dissolve in a lipid (fat) the easier and faster it will be transported into a cell. The rule was first outlined in the 1890s by Ernst Overton of the University of Zuerich. He declared that substances that dissolve in lipids pass more easily into a cell than those that dissolve in water.

But a team of electrochemists from the University of Warwick used a combination of a confocal microscope and an ultramicro-electrode to study what really happens when a chemical crosses a cell membrane.

Modern techniques allowed every step of the diffusion process to be directly examined. The results stunned the researchers as they produced the opposite results to those predicted by Overton.

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.

In fact, researchers saw that for these four acids the exact opposite is true: the easier it is for an acid to dissolve in a lipid, the slower it is transported across the membrane.

The research team will now use their technique to examine the diffusion into cells of a range of other chemicals.

The lead researcher on the study from the University of Warwick, Professor Patrick Unwin, said: 'We will now make observations with a range of other chemicals, and with other techniques, to further elucidate the molecular basis for our observations.

'Text books will have to be rewritten to revise a rule that has been relied on for over a century. Advanced techniques, such as the one we have developed, should give much clearer insight into the action of a wide range of drug molecules, which will be of significant interest to drug developers.'

The research is published in the Proceedings of the National Academy of Sciences (PNAS).