P-glycoprotein and its role in drug interactions (2023)


Efflux transporters, such as P-glycoprotein, play an important role in drug transport in many organs. In the intestine, P-glycoprotein pumps drugs back into the lumen, reducing their absorption.

Drugs that induce P-glycoprotein, such as rifampicin, may reduce the bioavailability of some other drugs. P-glycoprotein inhibitors, such as verapamil, increase the bioavailability of susceptible drugs.

Many, but not all, of the drugs that are transported by P-glycoprotein are also metabolized by cytochrome P450 3A4.

Important P-glycoprotein substrates include calcium channel blockers, cyclosporine, dabigatran etexilate, digoxin, erythromycin, loperamide, protease inhibitors, and tacrolimus. Prediction of clinically important interactions is difficult due to interindividual differences in drug transport.


P-glycoprotein is one of the drug transporters that determine the uptake and efflux of a number of drugs. This process affects their plasma and tissue concentrations and, ultimately, their final effects. The P-glycoprotein functions as a transmembrane flux pump, pumping its substrates from the inside to the outside of the cell. Medications that induce or inhibit P-glycoprotein may interact with other medications handled by the pump.


P-glycoprotein was first described in tumor cells. These cells had overexpression of P-glycoprotein, which reduced the access of cytotoxic drugs. Because this made the tumors resistant to various anticancer drugs, P-glycoprotein was also known as multidrug resistance protein 1. P-glycoprotein is also expressed in a variety of normal non-tumor tissues with excretory functions (small intestine, liver, and kidney).1and in blood tissue barriers (blood-brain barrier, blood-testis barrier, and placenta).2

(Video) P -Glycoprotein Enzymes Drug Interactions MADE EASY in 3 MINS

Together with the cytochrome P450 (CYP) family of enzymes, the concomitant expression of P-glycoprotein is thought to be an important evolutionary adaptation against potentially toxic substances. As an efflux transporter, it limits the bioavailability of orally administered drugs by pumping them back into the lumen. This promotes the elimination of the drug in the bile and urine and protects a number of tissues such as the brain, testis, placenta, and lymphocytes. Substrates for P-glycoprotein are a wide variety of structurally diverse compounds.2

drug absorption

The epithelial cell lining of the small intestine is not only a site for drug absorption, but also a major barrier to xenobiotic absorption. P-glycoprotein is found in the apical (luminal) membrane of the entire intestine from the duodenum to the rectum, with high expression in small intestinal enterocytes. It reduces the oral availability of the drugs that are its substrates.3,4

Like enzymes involved in drug metabolism, P-glycoprotein substrates can potentially act as inhibitors or inducers of its function. Inhibition of P-glycoprotein may result in increased bioavailability of the susceptible drug. Induction of P-glycoprotein reduces bioavailability.

drug distribution

Once a drug has reached the systemic circulation, the P-glycoprotein further limits penetration into various sensitive tissues. P-glycoprotein is also important to the blood-brain barrier as a defense against the penetration of toxins and drugs into the central nervous system.3

drug removal

P-glycoprotein has a modest role in drug clearance. It is expressed on the luminal membrane of proximal tubule cells in the kidneys. P-glycoprotein pumps drugs into the urine.

Drug interactions

P-glycoprotein is an important mediator of drug interactions.3The pharmacokinetics of a drug can be altered when it is administered together with compounds that inhibit or induce P-glycoprotein.3,5,6Inhibitors include clarithromycin, erythromycin, ritonavir, and verapamil. Inducers include rifampicin and St. John's wort.

P-glycoprotein has a very broad substrate spectrum similar to CYP3A4. It is involved in the transportation of drugs of different classes of drugs, including:

  • antineoplastic drugs, e.g. docetaxel, etoposide, vincristine
  • calcium channel blockers, e.g. amlodipine
  • calcineurin inhibitors, e.g. cyclosporine, tacrolimus
  • digoxin
  • macrolide antibiotics, e.g. clarithromycin
  • Protease inhibitors.

P-glycoprotein substrates can be divided into drugs that are not metabolized in humans, such as digoxin, and those that are substrates of both P-glycoprotein and drug-metabolizing enzymes, particularly CYP3A4.2,3 Since many P-glycoprotein substrates are also CYP3A4 substrates, and since P-glycoprotein inhibitors are also CYP3A4 inhibitors, many drug interactions are related to the inhibition or induction of both P-glycoprotein and CYP3A4. Drugs that are "targets" of such interactions include cyclosporine, tacrolimus, and rivaroxaban.3

Enterocytes, like hepatocytes, co-express the major drug-metabolizing enzyme CYP3A4 and the efflux transporter P-glycoprotein.7This creates a drug-metabolism efflux "alliance", which increases the exposure of the drug to metabolism by CYP3A4 through repeated cycles of uptake and efflux.2 Modification of this active barrier function by concomitant drug administration contributes to impaired absorption, increased interindividual differences in systemic drug concentrations, and probably increased risk of toxicity.4

Accurate prediction of potential drug interactions via P-glycoprotein is complicated by marked interindividual differences in bioavailability. This also affects drugs that are not metabolized in humans (fexofenadine, digoxin).2,4A better understanding of the role of genetics in transporter expression and function will contribute to a better understanding of interindividual and interethnic differences in drug disposition and effects.2

(Video) P-Glycoprotein and Drug Transport Part 1 of 2 with Dr. Michael Gottesman


P-glycoprotein is the most important drug transporter in reducing drug entry into the central nervous system. The over-the-counter antidiarrheal medication loperamide is a potent opioid, but has no opioid effects on the central nervous system at usual doses. This is because the P-glycoprotein prevents transport across the blood-brain barrier.

Concomitant administration of loperamide and a potent P-glycoprotein inhibitor, such as verapamil, may be associated with respiratory depression. This potentially dangerous effect on the central nervous system of such a widely used and readily available drug is of great interest. It raises safety concerns, but suggests that P-glycoprotein inhibition could be a novel strategy to overcome the blood-brain barrier to increase drug delivery to the brain.8


Induction or inhibition of intestinal P-glycoprotein appears to be a major mechanism underlying drug-drug interactions leading to reduced or elevated digoxin concentrations. Rifampicin and St. John's wort induce P-glycoprotein and thus reduce digoxin levels.

(Video) What is P-glycoprotein?

HIV-1 protease inhibitors

Effective treatment of HIV can be hampered by the P-glycoprotein located in cell membranes. Potential mechanisms include the following:

  • intestinal P-glycoprotein limits absorption of HIV protease inhibitors
  • HIV protease inhibitors are good substrates of P-glycoprotein, 9thus this limits their transfer across the blood-brain barrier, which may contribute to viral persistence and reduced efficacy
  • P-glycoprotein is also expressed on CD4 cells, the main target of anti-HIV drugs.


As dabigatran etexilate is a P-glycoprotein substrate, there is a potential for drug interactions involving drugs that act on P-glycoprotein. P-glycoprotein inhibitors such as ketoconazole, amiodarone, verapamil, Ticagrelor and clarithromycin may increase dabigatran peak plasma concentrations and subsequently significantly increase the risk of major bleeding.1


P-glycoprotein is an efflux transporter pump present in many organs and plays an important role in drug transport. Expression of P-glycoprotein can have important effects on drug absorption, distribution, and elimination. Although interactions with drug transporters may be clinically insignificant, it is important to be aware of potential transporter-related drug interactions. Central nervous system depression, HIV infection without adequate treatment, and transplant rejection are possible outcomes if these interactions occur. Knowledge of these potential interactions in at-risk patient groups can help ensure the provision of safe and effective treatment.

Conflict of interest: none declared

Other reading

Weekly Pharmacology. Complete drug reference table. San Antonio, TX: Pharmacology Weekly; 2012.www.pharmacologyweekly.com/content/pages/drug-reference table-cyp-p450-ugt-enzymes-transporters-ab[cited 2014 Jul 11]

(Video) Application of PBPK Modeling in Predicting P-glycoprotein-Mediated Drug-Drug Interactions

Self-assessment questions

The following statements are true or false.

Click anywhere on the panel to view the responses.

1. P-glycoprotein inhibitors increase the oral bioavailability of their substrates.

2. P-glycoprotein metabolizes dabigatran.

Answers to self-assessment questions

1. True

2. False


  1. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the P-glycoprotein multidrug resistance gene product in normal human tissues. Proc Natl Acad Sci USA 1987;84:7735-8.
  2. Importance of P-glycoprotein in blood tissue barriers. Trends Pharmacol Sci 2004;25:424-9.
  3. Konig J, Muller F. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 2013;65:944-66.
  4. Igel S, Drescher S, Murdter T, Heinkele G, Tegude H, Hofmann U. Increased absorption of digoxin in the human jejunum due to efflux inhibition mediated by intestinal transporters. Clin Pharmacokinet 2007;46:777-85.
  5. Ho HR. Transporter and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 2005;78:260-77.
  6. International Transport Consortium, Giacomini KM, Tweedie DJ, Brouwer KL, Benet LZ. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9:215-36.
  7. Canaparo R, Finnstrom N, Serpe L, Nordmark A, Muntoni E, Eandi M. Expression of CYP3A and glycoprotein P isoforms in human stomach, yellow and ileum. Clin Exp Pharmacol Physiol 2007;34:1138–44.
  8. Sadeque AJM, He H, Shah S. Enhancement of drug delivery to the brain by inhibition of P-glycoprotein. Clin Pharmacol Ther 2000;68:231-7.
  9. Leake B, Roden DM, Kim RB, Fromm MF, Wandel C, Wood AJ. Drug-binding P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998;101:289-94.
  10. Kawabata M, Yokoyama Y, Sasano T, Hachiya H, Yagishita A. Bleeding events and dabigatran-activated partial thromboplastin time in clinical practice. J Cardiol 2013;62:121-6.
(Video) What Is P Glycoprotein (1 of 2)


P-glycoprotein and its role in drug interactions? ›

The general function of P-glycoprotein is now known to protect the body from harmful substances by: Removing drugs absorbed in the intestines back into the gut lumen. Maintaining the integrity of the blood brain barrier. Removing drugs from the kidneys and liver into the urine and bile respectively.

What is P-glycoprotein and what is its role in drug interactions? ›

P-glycoprotein is one of the drug transporters that determine the uptake and efflux of a range of drugs. This process affects their plasma and tissue concentrations and ultimately their final effects. P-glycoprotein functions as a transmembrane efflux pump, pumping its substrates from inside to outside the cell.

What is the role of P-glycoprotein? ›

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition.

What is the role of P-glycoprotein in drug disposition? ›

P-glycoprotein (Pgp), which is coded by human MDR1 (multidrug resistance) gene, is an energy-dependent efflux pump that exports its substrates out of the cell.

What drugs are affected by P-glycoprotein? ›

Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus.

What are the three roles of glycoproteins? ›

Glycoproteins in the cell membrane have many vital roles including cell signaling, cell-cell recognition, and cell adhesion. Cell adhesion provides structural integrity, and cell-cell recognition helps the immune system recognize antigens from pathogens.

What is P-glycoprotein known as? ›

P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers.

What is the function of glycoprotein quizlet? ›

Glycoproteins are found on the surface of the lipid bilayer of cell membranes. Their hydrophilic nature allows them to function in the aqueous environment, where they act in cell-cell recognition and binding of other molecules.

Where is P-glycoprotein found in the body? ›

P-gp is located on the canalicular apical membrane of hepatocytes in the liver; on the brush border of proximal tubule cells in the kidney; and on the apical membrane of mucosal cells in the small intestine (3).

What drugs are glycoproteins? ›

Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, ...

What drug class is glycoprotein? ›

Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors are a class of drugs that work by preventing the formation of blood clots by inhibiting the action of platelets.

How does glycoprotein act as a receptor? ›

Glycoproteins act as receptors capturing ligands into cells like transport proteins responsible for ingestion of nutrients, structures mediating molecular recognition, molecular signaling and cellular interactions [99].

Which of the following functions is the most important for the glycoproteins? ›

Of the following functions, the glycoproteins and glycolipids of animal cell membranes are most important for: the ability of cells to recognize like a different cells.

What is the function of the peripheral protein? ›

Peripheral membrane protein is a protein that is found temporarily attached to the cell or mitochondrial membrane. Peripheral membrane proteins attach to the membrane but are not embedded in it. The peripheral membrane proteins function in support, communication, enzymes, and molecule transfer in the cell.

What type of transport is P-glycoprotein? ›

Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that, utilizes the energy of ATP hydrolysis to pump toxic xenobiotics out of cells. P-glycoprotein employs a most unusual molecular mechanism to perform this drug transport function.

What is glycoprotein and its role in immune response? ›

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex.

What is the impact of P-glycoprotein at the blood brain barrier? ›

P-glycoprotein (P-gp) is an efflux transporter expressed at the blood–brain barrier (BBB), which restricts the brain distribution of many drugs. Variability in P-gp function at the BBB may lead to variability in response to central nervous system (CNS)-acting drugs and/or CNS adverse effects.

What is a real life example of glycoprotein? ›

One example of glycoproteins found in the body is mucins, which are secreted in the mucus of the respiratory and digestive tracts. The sugars when attached to mucins give them considerable water-holding capacity and also make them resistant to proteolysis by digestive enzymes.

What drug binds to acid glycoproteins? ›

Alpha-1-acid glycoprotein binds neutral and basic drugs, examples of such drugs include diazepam, disopyramide, and chlorpromazine.

What receptors are glycoproteins? ›

Glycoprotein hormone receptors [thyrotropin (TSHr), luteinizing hormone/chorionic gonadotropin (LH/CGr), follicle stimulating hormone (FSHr)] are rhodopsin-like G protein-coupled receptors with a large extracellular N-terminal portion responsible for hormone recognition and binding.

What is the meaning of glycoprotein? ›

(gly-koh-PROH-teen) A protein that has sugar molecules attached to it.

What is the function of glycoproteins in the plasma membrane quizlet? ›

Most integral proteins are transmembrane proteins which span the entire plasma membrane. Glycoproteins play a crucial part in cell-cell recognition, and have important roles in protection and the immune response, reproduction, structural integrity and cell adhesion.

How do glycoproteins act as receptors? ›

Glycoproteins act as receptors capturing ligands into cells like transport proteins responsible for ingestion of nutrients, structures mediating molecular recognition, molecular signaling and cellular interactions [99].

Why do glycoproteins act as receptors? ›

Glycoproteins and glycolipids form receptors on the cell surface membrane, which are able to receive signals, such as hormones, from neighbouring cells or from the environment. This is then relayed to the inside of the cell to initiate specific cellular responses related to these messages.


1. P-Glycoprotein and Drug Transport Part 2 of 2 with Dr. Matthew Hall
(NIH Clinical Center)
2. p glycoprotein interactions
(Clinical pharmacy and beyond)
3. Drug Interaction (Part 01) = Pharmacokinetic and Pharmacodynamic Drug Interaction | Drug Interaction
(Solution- Pharmacy)
4. What Is P Glycoprotein (2 of 2)
(NEI Psychopharm)
5. P glycoprotein | Factors influencing drug absorption | Lippincott pharmacology
(Medical Lectures by Dr. Rizwana Raheel)
6. Drug Interactions: A Comprehensive Update
(BP International)


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