Protein-protein interactions of drug uptake transporters that are important for liver and kidney

Abstract

Drug uptake transporters are membrane proteins responsible for the trans-membrane transport of endo- and xenobiotics, including numerous drugs. They are important for the uptake of drugs into target tissues or into organs for metabolism and excretion. Many drug uptake transporters have a broad spectrum of structural-independent substrates, which make them vulnerable to drug-drug interactions. Recent studies have shown more and more complex pharmacokinetics involving transporters, and regulatory agencies now require studies to be performed to measure the involvement of transporters in drug development. A better understanding of the factors affecting the expression of transporters is needed. Despite many efforts devoted to the functional characterization of different drug uptake transporters, transporter in vitro to in vivo extrapolations are far from predicting the behavior under physiological conditions. There is an increasing number of uptake transporters demonstrated to form protein-protein interactions or to oligomerize. This raises the possibility that these interactions between or among transporters could help explaining the gap between in vitro and in vivo measurement of drug transporters. In this review, we summarized protein-protein interactions of drug uptake transporters that are important for pharmacokinetics, especially those in the liver and the kidneys.

Keywords: Drug transporter; Hepatocyte; OATP; Protein-protein interactions.

Figure 1:. Illustration of the interactions among liver uptake transporters.

Summary of the published protein-protein interactions at the basolateral membrane of human hepatocytes (left). A proposed membrane microdomain containing selected transporters is illustrated at right with the following color code: OATP1B1 (orange), OATP1B3 (blue), NTCP (green) and OCT1(red).

Figure 2:. Illustration of the interactions among renal uptake transporters.

Published protein-protein interactions at the basolateral membrane of renal tubular epithelial cells are summarized on the left. A proposed lipid domain with transporters that have been shown to interact with caveolin is illustrated at right: OAT3 (green) and OCTN2 (blue).