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 of the Warwick researchers suggest that the real transport rates could be up to 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 Zürich. He declared that substances that dissolve in lipids pass more easily into a cell than those that dissolve in water. He then set forth an equation that predicted how fast that diffusion would happen. One of the key parameters in that equation is K, which defines the lipophilicity (oil-liking nature) of the chemical. The higher the value of K, the faster the predicted cell permeation rate. For over a century, medicinal chemists have used this relationship to shape their studies and clinical trials.
A team of electrochemists from the University of Warwick used a combination of a confocal microscope and an ultramicroelectrode to study what happens when a chemical crosses a cell membrane. Advances in technology enabled them to position an ultramicroelectrode close to the membrane boundary (roughly 20 microns away) where it was used to generate a range of acids that should be able to diffuse relatively easily into a cell. Every step of the diffusion process was examined.
The results showed that While the acids did diffuse across a lipid membrane, they did so at rates that were diametrically opposite to the predictions of the Rule, i.e. the most lipophilic molecules were actually transported slowest. 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. However, researchers observed 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 research is published in the Proceedings of the National Academy of Sciences (PNAS) and is entitled “Quantitative visualization of passive transport across bilayer lipid membranes”.
Release Date: August 26, 2008
Source: University of Warwick
