Transporter-Mediated Drug Interactions

Transporter-mediated drug interactions occur when one drug alters the activity of a membrane transport protein - such as P-glycoprotein or the organic anion transporting polypeptides (OATPs) - that moves another drug across cell membranes in the gut, liver, kidney, or blood-brain barrier. By inhibiting or inducing these uptake and efflux transporters, a perpetrator drug can change the absorption, distribution, and elimination of a victim drug independently of any change in metabolism.

Definition

A transporter-mediated drug interaction is a change in the pharmacokinetics of one drug caused by another drug's effect on a membrane transport protein that mediates the uptake or efflux of the first drug across biological barriers.

Scope

This topic covers the major uptake and efflux transporter families relevant to drug disposition, the tissues where they govern absorption and elimination, how inhibition or induction of a transporter changes a substrate's exposure, and how these interactions are distinguished from enzyme-based ones. It is a mechanistic reference topic, not dosing guidance.

Core questions

• Which uptake and efflux transporters most influence drug disposition?
• How does inhibiting or inducing a transporter change a substrate's exposure?
• How can a transporter interaction be distinguished from a metabolic one?
• Where in the body do these transporters control absorption and elimination?

Key concepts

• Efflux transporters (P-glycoprotein, BCRP)
• Uptake transporters (OATPs, OATs, OCTs)
• Victim (substrate) and perpetrator drugs
• Barrier tissues: gut, liver, kidney, blood-brain barrier
• Transporter inhibition and induction
• Overlap of transport and metabolism
• Clinically important transporters of regulatory interest

Mechanisms

Membrane transporters fall broadly into efflux pumps of the ATP-binding cassette family, such as P-glycoprotein and BCRP, and uptake carriers of the solute carrier family, such as the OATPs, OATs, and OCTs. They are expressed at sites that control drug entry and exit - the intestinal wall, hepatocytes, renal tubules, and the blood-brain barrier - so changing their activity shifts where and how fast a drug moves (International Transporter Consortium, 2010). A perpetrator drug that inhibits an uptake transporter can reduce hepatic or renal clearance of a victim substrate and raise its plasma exposure, while inhibition of intestinal efflux can increase oral absorption; induction has the opposite effects. Because some drugs are handled by both transporters and metabolizing enzymes, transport and metabolism often act together, and consensus efforts have catalogued the transporters of greatest clinical importance (Giacomini et al., 2018; Zamek-Gliszczynski et al., 2022).

Clinical relevance

Transporter-mediated interactions are an established cause of clinically significant changes in drug exposure and are a recognised focus of drug-interaction evaluation and pharmacovigilance. This entry explains the underlying transport biology for reference and education; it describes mechanisms and is not a source of dosing or treatment recommendations.

Evidence & guidelines

The field is anchored by the International Transporter Consortium's white papers, which identify the transporters of clinical importance and inform regulatory expectations for evaluating transporter-based interactions during drug development (International Transporter Consortium, 2010; Giacomini et al., 2018; Zamek-Gliszczynski et al., 2022).

History

Although membrane transport had long been studied in physiology, its central role in drug disposition and interactions was consolidated in the 2000s, culminating in the International Transporter Consortium's 2010 synthesis that framed transporters as determinants of drug development. Successive consortium updates have extended the list of transporters considered clinically important.

Key figures

• Kathleen M. Giacomini
• Maciej J. Zamek-Gliszczynski
• Kim L. R. Brouwer

Seminal works

• itc-2010
• giacomini-2018
• zamek-gliszczynski-2022

Frequently asked questions

How does a transporter interaction differ from an enzyme interaction?

An enzyme interaction changes how fast a drug is chemically metabolized, while a transporter interaction changes how the drug is moved across membranes - affecting absorption, tissue distribution, and excretion - without necessarily altering its metabolism.

What does P-glycoprotein do in drug interactions?

P-glycoprotein is an efflux pump that pushes substrate drugs out of cells; inhibiting it can increase a drug's absorption and tissue exposure, whereas inducing it can lower exposure.