One of pharmacology's oldest underlying principles looks set to be overturned. New findings from chemists at the UK's University of Warwick appear to contradict the century-old 'Overton's Rule', which sets out how fast chemicals, such as medicines, can cross cell walls. The findings have major implications for drug development.

Many drugs need to get inside our cells to work effectively. While some molecules gain entry to the cell actively, via special structures embedded in the cell membrane, others gain access passively by permeating the cell's lipid membrane. Overton's Rule concerns molecules that get into cells via passive permeation.

Back in the 1890s, Swiss scientist Ernst Overton developed an equation which predicts how long it should take a given molecule to enter a cell. The resulting rule, which was named after its inventor, states that the easier it is for a chemical to dissolve in a lipid (fat), the faster it will be transported into a cell. One of the most important parameters in Overton's Rule is K, which defines the lipophilicity (oil-liking nature) of the chemical under investigation. The higher the value of K, the faster the rate of diffusion across the cell membrane. In other words, the more lipid-loving a chemical is, the faster it will get into a cell. In the century since Dr Overton first came up with his equation, medicinal scientists have relied on Overton's Rule when designing studies and clinical trials.

In this recent piece of research, the scientists used the latest technology to study in great detail exactly what happens when a molecule enters a cell. They used weak acids for their study; according to Overton's rule, these lipophilic molecules should cross the cell membrane relatively quickly. Their results are published online in the Proceedings of the National Academy of Sciences (PNAS).

What they observed shocked the researchers. Their results flew in the face of accepted wisdom and directly contradicted Overton's Rule. In short, the most lipophilic molecules took the longest to cross the membrane, and the least lipophilic acids were the fastest. The new rule suggests that Overton's Rule needs to be turned on its head; according to these results, the easier it is for a chemical to dissolve in a lipid, the slower it is transported across the cell membrane.

"This was a surprising and exciting finding. Our direct observations appear to totally undermine a key rule that has withstood the test of time for over a century," said lead researcher Professor Patrick Unwin.

"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."

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University of Warwick

Proceedings of the National Academy of Sciences (PNAS)

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