09/03/2013 - Reviews

Drug-transporter interaction testing in drug discovery and development

Péter Krajcsi, WORLD J PHARMACOL 2013 (1):35-46. Published online 2013 March 09 doi: 10.5497/WJP.v2.i1.35


The human body consists of several physiological barriers that express a number of membrane transporters. For an orally absorbed drug the intestinal, hepatic, renal and blood-brain barriers are of the greatest importance. The ATP-binding cassette (ABC) transporters that mediate cellular efflux and the solute carrier transporters that mostly mediate cellular uptake are the two superfamilies responsible for membrane transport of vast majority of drugs and drug metabolites. The total number of human transporters in the two superfamilies exceeds 400, and about 40-50 transporters have been characterized for drug transport. The latest Food and Drug Administration guidance focuses on P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 2 (OCT2), and organic anion transporters 1 (OAT1) and OAT3. The European Medicines Agency’s shortlist additionally contains the bile salt export pump, OCT1, and the multidrug and toxin extrusion transporters, multidrug and toxin extrusion protein 1 (MATE1) and MATE2/MATE2K. A variety of transporter assays are available to test drug-transporter interactions, transporter-mediated drug-drug interactions, and transporter-mediated toxicity. The drug binding site of ABC transporters is accessible from the cytoplasm or the inner leaflet of the plasma membrane. Therefore, vesicular transport assays utilizing inside-out vesicles are commonly used assays, where the directionality of transport results in drugs being transported into the vesicle. Monolayer assays utilizing polarized cells expressing efflux transporters are the test systems suggested by regulatory agencies. However, in some monolayers, uptake transporters must be coexpressed with efflux transporters to assure detectable transport of low passive permeability drugs. For uptake transporters mediating cellular drug uptake, utilization of stable transfectants have been suggested. In vivo animal models complete the testing battery. Some issues, such as in vivo relevance, gender difference, age and ontogeny issues can only be addressed using in vivo models. Transporter specificity is provided by using knock-out or mutant models. Alternatively, chemical knock-outs can be employed. Compensatory changes are less likely when using chemical knock-outs. On the other hand, specific inhibitors for some uptake transporters are not available, limiting the options to genetic knock-outs.

open_in_new Read the Source

Next: Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics

Previous: ABCG2 modulates chlorothiazide permeability—in vitro-characterization of its interactions