Drug Transporter Polymorphisms

Drug transporters are membrane proteins that move drugs and their metabolites into and out of cells, controlling absorption in the gut, uptake into the liver and kidney, and elimination. Inherited variants in the genes that encode these transporters - belonging chiefly to the ATP-binding cassette (ABC) efflux family and the solute carrier (SLC) uptake family - change how much drug reaches tissues and how it is cleared, making them an important part of pharmacogenomics.

Definition

Drug transporter polymorphisms are inherited sequence variants in the genes encoding membrane transport proteins that carry drugs across cell membranes, which alter the expression or function of these transporters and thereby influence drug absorption, tissue distribution, and elimination.

Scope

This topic covers the major drug-transporter families, the role of uptake and efflux transport in drug disposition, and the pharmacogenomic effects of common transporter polymorphisms. It is a reference description and does not provide dosing or individualized treatment advice.

Core questions

• Which transporters govern the uptake and efflux of a given drug?
• How do polymorphisms in transporter genes change drug exposure?
• How do transporters interact with metabolizing enzymes to shape overall disposition?

Key concepts

• Uptake transporters (solute carrier, SLC family)
• Efflux transporters (ATP-binding cassette, ABC family)
• P-glycoprotein (MDR1/ABCB1) multidrug efflux
• Organic anion transporting polypeptides (OATPs, e.g., OATP1B1/SLCO1B1)
• Tissue gatekeeping at gut, liver, kidney, and blood-brain barrier
• Genetic variation altering transporter expression or activity

Mechanisms

Transporters fall into two broad functional classes: uptake transporters of the solute carrier (SLC) family that carry drugs into cells, and efflux transporters of the ATP-binding cassette (ABC) family that pump drugs out using ATP (International Transporter Consortium, 2010). P-glycoprotein, an ABC efflux pump, limits drug absorption and protects tissues such as the brain by extruding a wide range of substrates (Ambudkar et al., 1999). On the uptake side, the organic anion transporting polypeptide OATP1B1 mediates hepatic uptake of many drugs, and common variants in its gene reduce that uptake and raise plasma concentrations of affected drugs (Niemi et al., 2011). Because transporters and metabolizing enzymes often act on overlapping substrates and in the same organs, the two systems jointly determine net drug disposition (Evans & McLeod, 2003).

Clinical relevance

Transporter polymorphisms help explain why some patients have higher drug exposure or altered tissue distribution, contributing to differences in response and to the risk of certain dose-related effects. This entry presents the mechanisms as a reference and is not a basis for individual dosing decisions.

Epidemiology

Functionally important transporter variants are common and differ in frequency across populations; for instance, the reduced-function SLCO1B1 variant affecting OATP1B1-mediated hepatic uptake varies in prevalence by ancestry (Niemi et al., 2011).

History

The multidrug-resistance efflux pump P-glycoprotein was identified in the 1970s-1980s in the context of cancer chemotherapy resistance and later recognised as a general determinant of drug disposition (Ambudkar et al., 1999). Through the 2000s, uptake transporters such as the OATPs were shown to be genetically polymorphic and clinically relevant (Niemi et al., 2011), and the International Transporter Consortium (2010) consolidated the field by defining the transporters of greatest importance for drug development.

Key figures

• Mikko Niemi
• Suresh Ambudkar
• Michael Gottesman
• William Evans
• Howard McLeod

Seminal works

• itc-2010
• ambudkar-1999
• niemi-2011

Frequently asked questions

What is the difference between uptake and efflux transporters?

Uptake transporters (mostly solute carrier, SLC, proteins) move drugs into cells, while efflux transporters (mostly ATP-binding cassette, ABC, proteins such as P-glycoprotein) pump drugs out of cells; together they control how much drug enters and stays in tissues.

Can transporter variants change drug levels even if metabolism is normal?

Yes - a polymorphism that reduces an uptake transporter or alters an efflux pump can raise or lower drug concentrations independently of how the drug is metabolised, because transport and metabolism are separate steps in disposition.