Drug transporters
Drug transporters are membrane proteins that actively move drugs into or out of cells — shaping oral bioavailability, hepatic uptake, renal secretion, and CNS penetration. Transporter-mediated drug interactions are now a major regulatory concern: FDA DDI guidance (2020) ↗ requires in vitro transporter screening for all new drugs. Key reference: ITC transporter DDI recommendations (NCBI) ↗.
Transporter families overview
Two major superfamilies govern drug transport:
ATP-Binding Cassette (efflux)
Use ATP hydrolysis to pump drugs out of cells. Members: P-gp (ABCB1), BCRP (ABCG2), MRP1–9 (ABCC1–9). Expressed on gut epithelium, BBB, liver (canalicular), kidney. Act as cellular defence against xenobiotics.
Solute Carrier (uptake + efflux)
Use electrochemical gradients or antiport mechanisms. Uptake members: OATP (SLCO), OCT (SLC22A), OAT (SLC22A). Efflux members: MATE (SLC47A). Critical for hepatic/renal drug clearance.
Key drug transporters and clinical relevance
| Transporter | Gene | Direction | Location | Key substrates | Key inhibitors |
|---|---|---|---|---|---|
| P-gp | ABCB1 | Efflux | Gut, BBB, liver, kidney | Digoxin, dabigatran, saquinavir, cyclosporine, loperamide | Amiodarone, verapamil, ketoconazole, ritonavir |
| BCRP | ABCG2 | Efflux | Gut, BBB, liver (canalicular), mammary gland | Rosuvastatin, methotrexate, topotecan, sulfasalazine | Elbasvir/grazoprevir, curcumin, grapefruit |
| OATP1B1 | SLCO1B1 | Uptake | Hepatocyte (basolateral) | All statins, repaglinide, rifampicin | Cyclosporine, gemfibrozil, elbasvir, rifampicin (inducer) |
| OATP1B3 | SLCO1B3 | Uptake | Hepatocyte (basolateral) | Statins, docetaxel, bosentan, olmesartan | Cyclosporine, rifampicin (inducer/inhibitor) |
| OCT2 | SLC22A2 | Uptake | Kidney proximal tubule (basolateral) | Metformin, cisplatin, dofetilide, creatinine | Cimetidine, trimethoprim, vandetanib |
| MATE1/2K | SLC47A1/2 | Efflux | Kidney proximal tubule (apical), liver | Metformin, creatinine | Pyrimethamine, cimetidine, trimethoprim |
| OAT1/3 | SLC22A6/8 | Uptake | Kidney proximal tubule (basolateral) | Tenofovir, methotrexate, furosemide, NSAIDs | Probenecid, diclofenac |
Comprehensive substrate/inhibitor/inducer lists are maintained in the FDA drug interaction table ↗ and the ITC (International Transporter Consortium) ↗ publications in Clinical Pharmacology & Therapeutics (NCBI) ↗.
Clinically significant transporter drug-drug interactions
Cyclosporine + statins (OATP1B1)
Cyclosporine is a potent inhibitor of OATP1B1/1B3 and P-gp. Co-administration with simvastatin or lovastatin increases statin AUC up to 15–20 fold → severe myopathy/rhabdomyolysis risk. Most statins are contraindicated with cyclosporine; rosuvastatin capped at 5 mg/day. DailyMed simvastatin ↗.
Amiodarone + digoxin (P-gp)
Amiodarone inhibits P-gp, reducing digoxin renal tubular secretion → digoxin plasma levels rise ~70%. Risk of digoxin toxicity (bradycardia, AV block, arrhythmia). Digoxin dose should be reduced by 50% on starting amiodarone; close TDM required. Related guide: TDM guide.
Trimethoprim + metformin (OCT2/MATE)
Trimethoprim inhibits OCT2 and MATE transporters, reducing renal secretion of metformin → metformin AUC increases ~40%. Also inhibits creatinine secretion via OCT2, causing a spurious serum creatinine rise without true GFR change — can falsely suggest renal impairment.
Rifampicin + OATP substrates (induction)
Rifampicin induces OATP1B1/1B3 acutely (inhibition in first doses, then induction after repeat dosing). Long-term rifampicin co-administration increases hepatic uptake clearance of statins, reducing their systemic exposure and potentially their efficacy. ITC review (NCBI) ↗.
Regulatory requirements for transporter assessment
The FDA 2020 DDI guidance ↗ and EMA 2012 DDI guideline ↗ require in vitro assessment of all new drugs for:
Prescribing information (FDA Section 12.3, EMA SmPC Section 4.5) must reflect clinically significant transporter interactions. See also our guide on drug-drug interactions ↗.
Frequently asked questions
What is the difference between an efflux transporter and an uptake transporter?
Uptake transporters (influx transporters) move drugs into cells from the extracellular compartment — e.g. OATP1B1 and OATP1B3 take up statins into hepatocytes, and OCT2 takes up metformin into renal tubular cells. Efflux transporters pump drugs out of cells back into the extracellular space or into bile/lumen — e.g. P-glycoprotein (P-gp/ABCB1) effluxes drugs out of intestinal epithelial cells (reducing absorption) and out of brain capillary endothelial cells (limiting CNS penetration). Both types can be inhibited or induced, causing drug-drug interactions.
Which drug-drug interactions are most clinically important due to transporter inhibition?
Key clinically important transporter DDIs: (1) OATP1B1/1B3 inhibition by cyclosporine → 15-fold increase in simvastatin AUC (rhabdomyolysis risk); (2) P-gp inhibition by amiodarone, verapamil, quinidine → increased digoxin plasma levels (toxicity); (3) OCT2/MATE inhibition by cimetidine, trimethoprim → reduced renal creatinine secretion (falsely elevated SCr, and metformin accumulation); (4) BCRP inhibition by elbasvir/grazoprevir → increased rosuvastatin AUC. FDA and EMA regulatory guidance now requires in vitro transporter screening for all new drugs.
Does P-glycoprotein affect drug absorption from the gut?
Yes — P-gp is highly expressed in intestinal epithelial cells (enterocytes) and acts as an efflux pump, expelling drug back into the intestinal lumen after it has been absorbed. This reduces net oral bioavailability for P-gp substrates. Inhibiting P-gp (e.g. with ketoconazole, grapefruit juice, ritonavir) increases absorption of substrates like saquinavir, cyclosporine, digoxin, and many other drugs. P-gp is also co-expressed with CYP3A4 in the gut wall, and these often act synergistically to limit drug exposure.
How do transporters affect drug penetration into the CNS?
The blood-brain barrier (BBB) expresses P-gp, BCRP, and several MRP efflux transporters on the luminal side of brain capillary endothelial cells. These pumps actively exclude many drugs from the CNS — including many anticancer agents (taxanes, vinca alkaloids), some antiretrovirals, and lopinavir. P-gp inhibition can enhance CNS drug delivery for CNS-targeted therapies. Genetic polymorphisms in ABCB1 (P-gp gene) affect CNS drug levels and have been studied in epilepsy pharmacoresistance.
What is the FDA/EMA regulatory requirement for transporter studies?
FDA (2020 DDI guidance) and EMA (2012 DDI guideline) require in vitro evaluation of new drugs for: P-gp, BCRP, OATP1B1, OATP1B3 (for hepatic uptake substrates/inhibitors), OCT1, OCT2, OAT1, OAT3, MATE1, MATE2K. If in vitro data suggest potential clinical relevance (using R-value or AUCR criteria), dedicated clinical DDI studies are required. The results must be reflected in the prescribing information (Section 12.3 Drug Interactions in FDA labelling).