What do drug transporters really do?

Abstract

Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication ('remote sensing and signalling') between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug-metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.

Figure 1. SLC and ABC drug transporters are expressed in most epithelial barriers

Barrier epithelia play a major part in homeostasis by regulating the transcellular movement of solutes between body fluid compartments (for instance, between blood and urine, blood and cerebrospinal fluid, or blood and bile). Members of the solute carrier (SLC) and ATP-binding cassette (ABC) transporter families have been found in a variety of barrier epithelial cells (as well as in other cell types), where they regulate the movement of small-molecule xenobiotics (such as drugs and toxins) and endogenous metabolites into and out of the various tissues and fluid compartments. Examples of the arrangement of drug transporters within several different barrier epithelial cell types are depicted here. These transporters maintain homeostasis and mediate processes important for pharmacokinetics and toxicokinetics. Although the subsets of drug transporters that are expressed vary depending on the tissue, the movement of small-molecule substrates between body fluid compartments requires the activity of both SLC (generally influx) and ABC (efflux) transporters. Selected members of the SLC family (namely, organic anion transporters (OATs), organic anion-transporting polypeptides (OATPs), organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs) and multidrug and toxin extrusion proteins (MATEs)) are shown in blue boxes, and members of the ABC family (multidrug-resistance proteins (MDRs), breast cancer-resistance protein (BCRP) and multidrug-resistance-associated proteins (MRPs)) are shown in green boxes. In certain cases, specific tissue expression has only been clearly established in humans or mice, and localization to apical or basolateral surfaces remains tentative. Note that in this figure, the common names of the transporters are used; for formal designations, please refer to the main text, tables and/or FIG. 2. Many other SLC and ABC drug transporters and their relatives are also expressed in these tissues but are not shown here.

Figure 2. SLC and ABC drug transporters that have been implicated in the handling of xenobiotics and drugs

Members of the solute carrier (SLC) and ATP-binding cassette (ABC) transporter families with roles in the absorption, disposition and elimination of xenobiotics and drugs have formal SLC and ABC designations as well as other designations that are commonly used in the field. The designations of many SLC and ABC drug transporters discussed in this article are clarified in this diagram. Within the SLC superfamily, members of the SLCO (also known as OATP and SLC21), SLC22 and SLC47 families have been shown to have key roles in drug transport. Transporters in the SLC22 family that are implicated in drug transport include members of the organic cation transporter (OCT), organic cation/carnitine transporters (OCTN) and organic anion transporter (OAT) families, as well as the uric acid transporter, URAT1 (SLC22A12). The SLC47 family has two members — SLC47A1 (also known as MATE1) and SLC47A2 (also known as MATE2, which has a kidney isoform MATE2K) — that have been implicated in drug transport. ABC transporters that have been implicated in drug handling can be divided into three subfamilies — namely, ABCB1 (also known as P-glycoprotein (PGP) or MDR1), the multidrug resistance-associated proteins (MRPs) of the ABCC family, and the breast cancer-resistance protein (BCRP; also known as ABCG2). Other transporters have also been implicated in drug transport but are not discussed in this article.

Figure 3. Reconstruction of metabolic networks from large-scale ‘omics’ data implicates drug transporters in metabolic pathways

a | One type of computational approach based on ‘omics’ data for connecting transporters and metabolic pathways is schematically represented. In this strategy, transcriptomic data derived from transporter knockout mice are analysed using genome-scale metabolic reconstruction tools^,–. This approach can be used to support a potential linkage between a specific transporter and certain metabolic pathways that can be further validated by in vitro and other assays. Metabolomics data from knockout mice are also very valuable for supporting predictions. An approach related to this was used to link SLC22A6 (OAT1)-mediated transport to several metabolic pathways. A number of other approaches have also been developed (not shown). b | The type of combined computational–wet-lab approach schematized in part a, once performed for multiple ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, may enable novel interpretations of the role of drug transporters in whole-body physiology, as well as in intracellular metabolism in specific tissues.