Efflux transporters such as P-glycoprotein play an important role in drug transport in many organs. In the gut, P-glycoprotein pumps drugs back into the lumen and decreases their absorption.
Drugs that induce P-glycoprotein, such as rifampicin, can reduce the bioavailability of some other drugs. P-glycoprotein inhibitors such as verapamil increase the bioavailability of sensitive drugs.
Many, but not all, drugs that are transported by P-glycoprotein are also metabolized by cytochrome P450 3A4.
Important substrates of P-glycoprotein include calcium channel blockers, cyclosporine, dabigatran etexilate, digoxin, erythromycin, loperamide, protease inhibitors and tacrolimus. Predicting clinically important interactions is difficult due to inter-individual 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 ultimate effects. P-glycoprotein acts as a transmembrane efflux pump, pumping its substrates from inside to outside the cell. Drugs that induce or inhibit P-glycoprotein may interact with other drugs being handled by the pump.
P-glycoprotein was first described in tumor cells. These cells had overexpression of P-glycoprotein, which reduced access of cytotoxic drugs. Since this made the tumors resistant to various cancer drugs, P-glycoprotein was also referred to as multidrug resistance protein 1. P-glycoprotein is also expressed in a variety of normal, non-tumorous tissues with excretory functions (small intestine, liver and kidney).1and at blood-tissue barriers (blood-brain barrier, blood-testis barrier and placenta).2
Along with the family of cytochrome P450 (CYP) enzymes, co-expression of P-glycoprotein is believed to be an important evolutionary adaptation against potentially toxic agents. As an efflux transporter, it limits the bioavailability of orally administered drugs by pumping them back into the lumen. This promotes excretion of the drug in the bile and urine and protects a number of tissues such as the brain, testicles, placenta and lymphocytes. The substrates for P-glycoprotein are a wide variety of structurally diverse compounds.2
intake of medication
The epithelial cell lining of the small intestine is not only a site for drug absorption, but also an important 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 the enterocytes of the small intestine. It reduces the oral availability of drugs, which are its substrates.3,4
Like the enzymes involved in drug metabolism, substrates of P-glycoprotein 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 decreases bioavailability.
Once a drug has reached the systemic circulation, P-glycoprotein further restricts penetration into a number of sensitive tissues. P-glycoprotein is also important for the blood-brain barrier as a defense against toxins and drugs entering the central nervous system.3
elimination of drugs
P-glycoprotein plays a modest role in drug clearance. It is expressed in the luminal membrane of proximal tubular cells in the kidneys. P-glycoprotein pumps drugs into the urine.
Interactions with other drugs
P-glycoprotein is an important mediator of drug interactions.3The pharmacokinetics of a drug can be altered when co-administered 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.
Similar to CYP3A4, P-glycoprotein has a very broad substrate spectrum. It is involved in the transport of drugs from various drug classes, including:
- antineoplastic drugs e.g. docetaxel, etoposide, vincristine
- Calcium channel blockers e.g. amlodipine
- Calcineurin-Inhibitoren, z.B. Cyclosporin, Tacrolimus
- Makrolidantibiotika z.B. Clarithromycin
- protease inhibitors.
The substrates of P-glycoprotein can be further divided into drugs that are not metabolised in humans, such as digoxin, and those that are substrates of both P-glycoprotein and drug-metabolizing enzymes, particularly CYP3A4.2,3 Because many P-glycoprotein substrates are also substrates of CYP3A4, and because P-glycoprotein inhibitors are also inhibitors of CYP3A4, many drug-drug interactions are related to the inhibition or induction of both P-glycoprotein and CYP3A4. Drugs that are "objects" of such interactions include ciclosporin, tacrolimus and rivaroxaban.3
Enterocytes, like hepatocytes, simultaneously express the main drug-metabolizing enzyme CYP3A4 and the efflux transporter P-glycoprotein.7This creates a drug-efflux-metabolism "alliance" that increases drug exposure to metabolism by CYP3A4 through repeated cycles of absorption and efflux.2 Alteration of this active barrier function by co-administered drugs contributes to altered absorption, increased inter-individual differences in systemic drug concentrations and likely to an increased risk of toxicity.4
Accurate prediction of potential P-glycoprotein drug-drug interactions is complicated by marked inter-individual differences in bioavailability. This also applies to medicinal products that are not metabolised in humans (fexofenadine, digoxin).2,4A better knowledge of the role of genetics in transporter expression and function will contribute to a better understanding of inter-individual and inter-ethnic differences in drug disposition and action.2
P-glycoprotein is the main drug transporter to reduce the entry of drugs into the central nervous system. The over-the-counter antidiarrheal drug loperamide is a powerful opiate but has no opioid effects on the central nervous system at usual doses. This is because P-glycoprotein prevents transport across the blood-brain barrier.
Concomitant administration of loperamide and a strong P-glycoprotein inhibitor such as verapamil may be associated with respiratory depression. This potentially dangerous effect on the central nervous system from such a widely used and readily available drug is of great interest. It raises safety concerns but suggests that inhibiting P-glycoprotein could be a new strategy to cross 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 interactions leading to decreased or increased digoxin concentrations. Rifampicin and St. John's wort induce P-glycoprotein and thereby decrease levels of digoxin.
HIV-1 protease inhibitors
Effective treatment of HIV can be hampered by P-glycoprotein, which is found in cell membranes. Possible mechanisms include the following:
- Gut P-glycoprotein limits absorption of HIV protease inhibitors
- HIV protease inhibitors are good P-glycoprotein substrates, 9thus, this limits their transmission across the blood-brain barrier, which may contribute to viral persistence and reduced efficacy
- P-glycoprotein is also expressed in CD4 cells, the main target of anti-HIV drugs.
Since dabigatran etexilate is a substrate of P-glycoprotein, there is a potential for interactions with other medicinal products that affect P-glycoprotein. P-glycoprotein inhibitors such as ketoconazole, amiodarone, verapamil, ticagrelor and clarithromycin may increase dabigatran peak plasma concentrations and consequently lead to a significantly increased risk of major bleeding.1
P-glycoprotein is an efflux transporter pump that is present in many organs and plays an important role in drug transport. P-glycoprotein expression may have important effects on drug absorption, distribution, and excretion. Although drug transporter interactions may be clinically insignificant, it is important to be aware of potential transporter-related drug interactions. Central nervous system depression, undertreated HIV infection, and transplant rejection are potential outcomes when these interactions occur. Awareness of these potential interactions in at-risk patient populations can help ensure safe and effective treatment.
Conflict of interest: none stated
Pharmacology weekly. Comprehensive drug reference table. San Antonio, TX: Pharmacology Weekly; 2012www.pharmacologyweekly.com/content/pages/drug-reference table-cyp-p450-ugt-enzymes-transporters-ab[as of July 11, 2014]
The following statements are either true or false.
Click anywhere in the panel to get the answers.
1. Inhibitors of P-glycoprotein increase the oral bioavailability of its substrates.
2. P-glycoprotein metabolizes dabigatran.
Answers to self-assessment questions
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- Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 2004;25:424-9.
- Konig J, Muller F. Transporters and drug interactions: Important determinants of drug disposition and action. Pharmacol. Rev 2013; 65:944-66.
- S. Igel, S. Drescher, T. Murdter, G. Heinkele, H. Tegude, U. Hofmann. Clin Pharmacokinet 2007;46:777-85.
- Hey RH. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 2005;78:260-77.
- International Transporter Consortium, Giacomini KM, Tweedie DJ, Brouwer KL, Benet LZ. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9:215-36.
- Canaparo R, Finnstrom N, Serpe L, Nordmark A, Muntoni E, Eandi M. Expression of CYP3A isoforms and P-glycoprotein in human stomach, jejunum and ileum. Clin Exp Pharmacol Physiol 2007;34:1138-44.
- Sadeque AJM, He H, Shah S. Increased drug delivery to the brain by P-glycoprotein inhibition. Clinic Pharmacol. thermal 2000; 68:231-7.
- Leake B, Roden DM, Kim RB, Fromm MF, Wandel C, Wood AJ. The drug transporter P-glycoprotein limits the oral uptake and entry of HIV-1 protease inhibitors into the brain. J.Clin. invest 1998; 101:289-94.
- Kawabata M, Yokoyama Y, Sasano T, Hachiya H, Yagishita A. Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice. J Cardiol 2013;62:121-6.