Copyright ©2013 Baishideng. All rights reserved.
World J Pharmacol. Mar 9, 2013; 2(1): 35-46
Published online Mar 9, 2013. doi: 10.5497/wjp.v2.i1.35
Drug-transporter interaction testing in drug discovery and development
Peter Krajcsi
Peter Krajcsi, Solvo Biotechnology, R and D, 2040 Budaors, Hungary
Author contributions: Krajcsi P solely contributed to this paper.
Supported by FP7 IMI MIP-DILI: Mechanism-based integrated systems for the prediction of drug-induced liver injury, FP7 Eustroke, Health-F2-2008-202213: European Stroke Research Network; TUDAS-1-2006-0029, OMFB-00505/2007: Development of HTS kit for analyzing transporter-drug interactions using cholesterol treated insect-cells expressing human MXR transporter, GOP-1.1.1-11-2011-0017: Integrated preclinical tools for the determination and the enhancement of drug absorption
Correspondence to: Peter Krajcsi, PhD, Solvo Biotechnology, R and D, 2040 Budaors, Hungary.
Telephone: +36-23-503940 Fax: +36-23-503941
Received: August 21, 2012
Revised: January 8, 2013
Accepted: January 29, 2013
Published online: March 9, 2013

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.

Keywords: ATP-binding cassette transporter, Solute carrier, Drug efflux, Drug uptake, Absorption-distribution-metabolism-excretion-toxicity, Regulatory guidance, ATPase, Vesicular transport, Monolayer assay, In vivo