Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs
Affiliation:
1. Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstr. 6 , D-97070 Würzburg , Germany 2. Department of Molecular Plant Physiology and Biophysics, Julius von Sachs Institute, University of Würzburg , D-97082 Würzburg , Germany
Abstract
Abstract
In vitro evaluation of drugs for interaction with transporters is essential during drug development. As polyspecific organic cation transporters (OCTs) are critical for pharmacokinetics of many cationic drugs, in vitro testing of human OCT1 and human OCT2 is recommended. In the currently applied tests it is determined whether uptake of one model cation in stably transfected epithelial cells is inhibited using a substrate concentration in the micromolar range. In this review experimental evidence for the existence of low- and high-affinity cation binding sites in OCTs that may interact with drugs is compiled. Most data were obtained from studies performed with rat Oct1. Whereas overlapping low-affinity cation binding sites are directly involved in transport, the high-affinity cation binding sites may induce allosteric inhibition of transport. Remarkably, high-affinity inhibition is only observed when uptake is measured using nanomolar substrate concentrations far below the respective K
m values. Affinities of inhibitors are dependent on molecular structure and concentration of the employed substrate. Because the currently applied in vitro tests for identification of interaction of novel drugs with OCTs do not consider the influence of substrate structure and are not capable of identifying high-affinity inhibition, more sophisticated testing protocols are proposed.
Funder
Deutsche Forschungsgemeinschaft
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
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