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   from the issue of December 16, 2004

     
 
Technique could benefit drug development

Techniques devised by UNL chemist David Hage will give pharmaceutical companies a powerful new tool for developing, testing and targeting dosages for drugs.

Hage, with former doctoral student Jianzhong Chen, published the article "Quantitative Analysis of Allosteric Drug-protein Binding by Biointeraction Chromatography" in the November issue of Nature Biotechnology. The importance of this work lies in the word "quantitative," because previous efforts in this field have been qualitative, or descriptive.

Hage's paper studies an effect known as an allosteric interaction, which is important in many biological processes. This term refers to the effect of one molecule on another when both bind to different regions of a common agent, such as a protein.

Hage's paper looks at how drugs bind to the protein human serum albumin (HSA). This protein has many sites where drugs can interact, and hundreds of drugs can bind to it. Hage also looked at HSA because it is the most abundant protein in blood, where it acts as a carrying agent for molecules such as fatty acids and drugs as they travel through the body.

Hage's paper asks, "How does the binding of one drug with HSA affect the binding of a second drug with the same protein?" In this situation, the second drug may cause the first drug's binding to become stronger or weaker, creating an allosteric effect. Such a process is important since it can be a source of drug-drug interactions in the body.

The technique Hage used for analyzing drug-protein binding is biointeraction chromatography. Chromatography is a way of separating chemicals by passing them in a liquid through a column that contains a layer or coating known as the stationary phase. In Hage's study, the protein HSA was used as the stationary phase and the liquid passing through the column was a buffer that mimicked the environment of drugs in blood. One drug was continuously introduced onto this column in the buffer, where it could bind with HSA.

A small quantity of a second drug was then introduced onto the same column. The effect of the first drug on the second was examined by looking at how the time of passage for the second drug through the column changed with the applied concentration of the first. By performing this experiment at several concentrations for the applied drug, the presence of an allosteric interaction between the two drugs could be determined and the extent of this interaction could be measured.

Drugs that Hage has tested in this matter include ibuprofen, a common anti-inflammatory agent, and several benzodiazepines, which are used as sedatives and anti-convulsants. These and many other drugs in blood are present in both a form that is bound to proteins such as HSA and in an unbound form that can bind to receptors or cross cell membranes to create a therapeutic effect. This drug-protein binding acts as a mechanism to control the elimination, metabolism and release of such drugs in the body.

About half of the 1,500 most common drugs are present in a form that is more than 90 percent bound to blood proteins, with most of this binding taking place with HSA. For this reason, pharmaceutical companies must always consider such binding as they determine how fast a drug will get into the body, how fast it will be eliminated, and how fast it will produce an effect. This will determine the size of the drug's dose and the length of time between doses. All of these items will also be affected by the presence of an allosteric effect between drugs on HSA or other blood proteins.

Biointeraction chromagraphy has been used by Hage's group and others over the last 10 years to qualitatively examine allosteric systems. In Hage's Nature Biotechnology article, a new theoretical method was described that allowed quantitative information to also be obtained through this technique.

According to Hage, "A unique thing about this particular approach is that we can look at an allosteric effect between two compounds in either direction. That is, the effect of drug A on drug B and drug B on drug A can be examined separately." Before this, scientists examining allosteric effects had to use mixtures of compounds and study their combined influence.

This ability to quantify the extent of drug-drug interactions should make it possible for chemists to better understand how proteins bind to drugs in blood, giving rise to better delivery systems for drugs and the design of new treatment methods. This method may help doctors move to a more individualized approach to medicine in which a drug is prescribed based on the patient's specific symptoms, blood chemistry and other medications.


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