Question 1

What is a drug efflux pump?

Accepted Answer

Drug efflux pumps are membrane-bound transporter proteins that actively move drugs and other xenobiotics out of cells, reducing intracellular drug accumulation. They belong to the ABC (ATP-Binding Cassette) superfamily of transporters, using ATP hydrolysis to drive substrate transport against concentration gradients. Clinically important efflux pumps include: P-glycoprotein (P-gp, encoded by ABCB1/MDR1) — the most extensively characterised; breast cancer resistance protein (BCRP, encoded by ABCG2); multidrug resistance-associated protein 2 (MRP2, encoded by ABCC2); and MRP3 (ABCC3). P-gp is expressed on intestinal enterocytes (reducing oral absorption), blood-brain barrier endothelium (limiting CNS penetration), hepatocytes (biliary excretion), and renal tubules (urinary excretion). Efflux pumps are a primary mechanism of drug resistance in cancer cells and pathogens, and are important mediators of clinically significant drug-drug interactions when co-administered with inhibitors or inducers.

Question 2

What are the most clinically important P-glycoprotein drug interactions?

Accepted Answer

P-gp inhibitors increase plasma concentrations of P-gp substrates by reducing intestinal efflux (increased absorption) and/or reducing hepatic/renal efflux (reduced elimination). Major clinical examples: (1) Digoxin + P-gp inhibitors (dronedarone, amiodarone, quinidine, verapamil, clarithromycin, itraconazole, ritonavir) — digoxin concentrations increase 1.5–4-fold, risking toxicity (arrhythmia, nausea); digoxin has a narrow therapeutic index and is an FDA-designated P-gp sensitive substrate. Dose reduction of digoxin (typically 30–50%) required. (2) Dabigatran + P-gp inhibitors — dabigatran is a pure P-gp substrate (not CYP metabolised); dronedarone, amiodarone, verapamil, clarithromycin increase dabigatran exposure 1.6–2.5-fold, increasing bleeding risk; dose reduction required with certain inhibitors. (3) Fexofenadine — near-pure P-gp/OATP substrate; erythromycin and ketoconazole inhibit both P-gp and OATP, increasing fexofenadine AUC 3-fold. P-gp induction (rifampicin, St John's wort, carbamazepine) reduces substrate exposure: rifampicin + digoxin reduces digoxin AUC by ~30%.

Question 3

How do BCRP and MRP2 efflux pumps affect drug pharmacokinetics?

Accepted Answer

BCRP (ABCG2) is highly expressed at the intestinal brush border, hepatic canalicular membrane, renal proximal tubule, blood-brain barrier, and placenta. Clinically relevant substrates include rosuvastatin, atorvastatin acid (to lesser extent), sulfasalazine, methotrexate, and irinotecan active metabolite SN-38. BCRP inhibitors include elacridar (experimental), gefitinib, lapatinib, pantoprazole, and rifampicin (complex with induction of CYP3A4). Important BCRP DDI: rosuvastatin + eltrombopag or lapatinib increase rosuvastatin AUC 1.5–2.5-fold (myopathy risk). MRP2 (ABCC2) mediates biliary excretion of glucuronide and sulfate conjugates, methotrexate, and some statins. MRP2 genetic variants (ABCC2 c.1249G>A) reduce biliary drug excretion. MRP2 inhibition by cyclosporin reduces biliary methotrexate excretion, increasing systemic toxicity. Both BCRP and MRP2 are regulated by pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR), meaning rifampicin and other PXR activators can both induce efflux (reducing drug concentrations) and sometimes induce CYP3A4 simultaneously.

Question 4

What is the role of efflux pumps in drug resistance?

Accepted Answer

Overexpression of efflux pumps is a primary mechanism of multidrug resistance (MDR) in cancer cells and pathogenic microorganisms. In cancer: P-gp overexpression (encoded by MDR1/ABCB1 gene) effluxes chemotherapy drugs — doxorubicin, vincristine, paclitaxel, etoposide — reducing intracellular concentrations below cytotoxic thresholds. BCRP overexpression contributes to resistance to irinotecan, methotrexate, imatinib, and gefitinib. P-gp overexpression is measurable by immunohistochemistry or RT-PCR and correlates with poor prognosis in AML, breast, and ovarian cancer. P-gp inhibitor strategies (verapamil, cyclosporin D analogue PSC-833, elacridar GF120918, tariquidar XR9576) were extensively studied in clinical trials to reverse MDR — most failed due to toxicity or inability to achieve sufficient efflux inhibition at tolerated doses. In bacteria: efflux pumps (AcrAB-TolC in Enterobacteriaceae, MexAB-OprM in Pseudomonas, NorA in Staphylococcus) extrude antibiotics — fluoroquinolones, tetracyclines, beta-lactams — and contribute to intrinsic and acquired resistance. Efflux pump inhibitor research for pathogens remains active.

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