Intelligent Drug Development Applied to Drug Transporters

Gerald Clarke

Drug development is growing up. Sophisticated, standardised, smart methods of developing new chemical entities (NCEs) are now the order of the day. No topic shows this better than drug transporter proteins.

Transport proteins are important to maintaining life. There are more than 1000 different types of them to be found in the body, where they are expressed at different levels in different tissues. These transporters evolved to take in nutrients from their surrounding environment and remove waste products and molecules which may damage the cell. Drugs, being molecules in a cell’s environment are subject to the same bullying around that cells do to control their environment as best they can.

This makes these transporters very important for studying how drugs enter important parts of the body. Bioavailability and ADME are important issues in drug effectiveness and transporters are especially relevant in studies of drug safety. Transporters affect safety through how drugs are dealt with by the body (pharmacokinetics) and through drug-drug-interactions.

In cancer and antibiotics for example, much work has been done on efflux transporters, which pump drugs out of the cell and so pose a challenge to ensuring that enough drug can get to where it is needed. However the focus has shifted to influx transporters, which bring molecules into the cell. Since different tissues express different levels of these transporters, developers can create specific NCEs which will be preferentially transported into the desired tissues. If these transporters can be taken advantage of, then cells can be ‘tricked’ into transporting the drug into the cell and working for us instead of against us.

In the development of new drugs, there are currently seven classes of transporters which are clinically relevant and when developing a new small molecule drug, regulators require that these seven are studied for any effects on drug safety. The International Transporters Consortium has now recommended that five new transporter classes are added to these studies. So does this mean that drug developers will now have to almost double the amount of drug transporter experiments that they have to perform? The new thinking on this question is that depending on the disease the drug it in development for, not all of them needs to be tested as they will not all be relevant. So in light of this, how can regulators and researchers agree on a smarter, more strategic way to ensure that drugs are safe and also that time isn’t wasted performing unnecessary experiments?

At the moment, results in vitro are not always as closely linked to in vivo results as could be possible. Current in vivo in vitro correlations (IVIVC) rely on models which do not perform as well as they could and these need to be improved. Current models of human morbidities include animal studies which, although they model some aspects of a disease, are still not often directly comparable to progression in humans.  Additional methods to improve IVIVC also include utilising more relevant cell-based, pharmacogenomic and structural biology approaches.

Pharmacogenomics is emerging as a promising field where several drugs including warfarin, anti-retrovirals and anti-tuberculosis therapies are known to be affected by genetic changes. Genes can differ between people and populations and even single nucleotide polymorphisms (SNPs) can affect how a drug interacts with a protein.  As a protein’s structure is reliant on its genetic sequence, analysing this creates a route to creating computer algorithms of how a transporter’s structure affects its function. These structure-function activity relationships (SARs) can then feed into better models of how drugs interact with transporters at the plasmalemma.  With the use of SARs in computational modelling, SNPs can be taken into account much more easily than in less dynamic models such as animal or cellular models. 

Another interesting issue around SARs is the tantalising prospect of being able to tailor dosing schedules for specific populations and even specific patients.  In a recent study led by Professor Andrew Owen of the University of Liverpool, an SNP carried by black Africans carry, was identified which reduces their exposure to the front-line anti-tuberculosis drug rifampicin.  This informed the recommendation that dosing should be reconsidered; a direct and measurable effect of taking SNPs into account to improve clinical results.  This points to the way in which modern medicine is headed towards a more stratified, personalised approach. With research into this field, in the future, a patient may be able to get a drug which they know will be safe, effective and perfectly suited to them.