Background

Drug transporters have gained prominent attention from almost everyone involved in drug development across the globe in the last two decades. Researchers now have a fair understanding of the vital role played by drug transporters in drug absorption, distribution, metabolism and excretion (ADME). Attention has been drawn towards their involvement in drug interactions and toxicity. Improvement in clinical translation of in vitro and preclinical transport studies and increased impact of regulatory authorities for better understanding of transport interactions (draft EMEA guidance and 2010 ITC whitepaper) are also stressed.

A range of various drug transporters is present in the human body. Most important of these include transporters expressed particularly in the endothelium of the blood–brain barrier and in the epithelia of the liver, intestine, and kidney during drug development. These drug transporters are specific to their substrates. However, the number of substrates specific to each transporter may vary. For example, a transporter may be specific for only one substrate while another may act as a transporter for three substrates. At a particular site, distribution of each of these transporters varies, entailing the different physiological functions and sometimes the pathological reaction. Lack or absence of these transporters can result in numerous genetic disorders. The bioavailability of drugs with less permeability and absorption can be enhanced by the use of transporters involved in the absorption or else by restricting the transporters required for the efflux system.

Thanks to fresh developments in molecular biology in gene cloning and other techniques, molecular level characteristics and distribution of transporters can be studied. Over the years, the major cause of failure for late stage therapeutic entities during drug development has been drug-induced organ toxicity. In vitro screening of molecular compounds can be done to ascertain the effect of drugs on various pathways or mechanisms that might be linked to drug toxicity. However, very few negative in vivo outcomes can be predicted in this manner; as in the case for most of the models, the in vivo conditions cannot be replicated.

The two major conditions required to determine the organ specificity for toxicity are increasing the concentration and delivery of drugs to the target. Much progress has already been made in deducing the role of these drug transporters in drug safety and efficacy. For the human genome, over hundreds of transporters have been discovered. Examples include the two most important superfamilies, namely, the ATP binding cassette and the solute carrier (abbreviated as ABC and SLC, respectively).

Since a lot of research has been done with focus on interaction of drugs and their metabolites, scientists have simultaneously developed a huge range of literature on the topic. Several of these studies suggest the in vivo role of drug transporters in the drug’s disposition, efficacy and some negative responses. Models for in vivo demonstration of the role of drug transporters include a number of animal species, commonly knockout (KO) mice. In humans, loss-of-function genetic variants have also been used. The in vivo role of many ABC and SLC transporters has been elucidated using such studies. Many such studies have proved the role of transporters along with several drug-metabolizing enzymes (DMEs) during ADME. Clinical pharmacokinetic drug-drug interaction studies also support genetic polymorphism of DMEs.

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