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 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

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

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.

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

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

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.

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

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]