Transporter-Mediated Drug Action

## Introduction

Membrane transporters are proteins that move drugs, nutrients, and endogenous substances across biological membranes against or along concentration gradients. They serve dual roles in pharmacology: as drug targets (where inhibition produces the therapeutic effect) and as determinants of drug disposition (affecting oral absorption, tissue distribution, and renal/biliary elimination).

## Major Transporter Families

### ABC Transporters (Efflux Pumps)

ATP-binding cassette transporters use ATP hydrolysis energy to pump substrates out of cells against concentration gradients. **P-glycoprotein (P-gp/MDR1/ABCB1)** is the most clinically important efflux transporter, expressed at intestinal epithelium (limiting oral drug absorption), the blood-brain barrier (restricting CNS drug penetration), renal proximal tubules (promoting drug excretion), and biliary canaliculi (facilitating biliary elimination).

**BCRP (ABCG2)** and **MRP2 (ABCC2)** are additional clinically important efflux transporters with overlapping but distinct substrate profiles.

### SLC Transporters (Uptake Carriers)

Solute carrier transporters facilitate uptake into cells, often using sodium or proton gradients. **OATPs** transport statins into hepatocytes where they inhibit HMG-CoA reductase. **OCT1/OCT2** mediate metformin uptake into hepatocytes and renal tubular cells. **SERT** (serotonin transporter) and **DAT** (dopamine transporter) recycle neurotransmitters from the synaptic cleft.

## Transporters as Drug Targets

Several major drug classes act primarily by inhibiting membrane transporters:

- **SSRIs** (fluoxetine, sertraline): Block SERT, increasing synaptic serotonin for depression
- **Cocaine**: Simultaneously blocks DAT, NET, and SERT
- **Loop diuretics** (furosemide): Inhibit NKCC2 cotransporter in the loop of Henle
- **Probenecid**: Inhibits OAT, reducing renal uric acid reabsorption in gout
- **Dapagliflozin**: Inhibits SGLT2, preventing renal glucose reabsorption in diabetes

## Transporter Drug Interactions

P-gp inhibitors (verapamil, cyclosporine, amiodarone) increase digoxin plasma levels by blocking its intestinal efflux and renal secretion. OATP1B1 inhibitors (cyclosporine, gemfibrozil) increase statin plasma concentrations by blocking hepatic uptake, raising the risk of statin myopathy and rhabdomyolysis.

## Key Takeaways

- ABC transporters efflux drugs out of cells; SLC transporters mediate cellular uptake
- Major drug classes (SSRIs, diuretics, SGLT2 inhibitors) act by transporter inhibition
- P-gp at the blood-brain barrier and intestine critically controls drug exposure
- Transporter drug interactions can be as clinically significant as CYP interactions