P-glycoprotein (P-gp) is a protein that acts as a pump within the body, located in the cell membranes of various tissues. It plays a significant role in regulating the movement of substances, including many medications, across these membranes. A “substrate” in this context refers to any molecule that P-gp recognizes, binds to, and actively transports out of cells. This pumping action can influence how effectively drugs are absorbed, distributed, and eliminated from the body.
What is P-glycoprotein?
P-glycoprotein, also identified as ABCB1 or MDR1, functions as an “efflux pump,” meaning it actively expels substances from inside cells. This protein is a member of the ATP-binding cassette (ABC) transporter family, which utilizes energy from ATP hydrolysis to move a wide variety of compounds across cell membranes. P-gp is a large protein, approximately 170 kilodaltons (kDa) in size, composed of two symmetrical halves, each containing six transmembrane helices and a nucleotide-binding domain.
P-gp is widely distributed throughout the human body, serving as a protective barrier in several key locations. It is highly expressed in the intestinal epithelium, liver, kidneys, and at the blood-brain barrier. This widespread distribution allows P-gp to play a role in detoxification and the regulation of various compounds within the body.
How P-gp Recognizes and Transports Molecules
P-gp is known for its broad substrate specificity, meaning it can interact with and transport a wide range of chemically diverse compounds. These substrates often share characteristics such as being hydrophobic and having a positive charge, along with specific hydrogen bond acceptor patterns.
The mechanism by which P-gp transports molecules is an energy-dependent process, powered by the binding and hydrolysis of ATP (adenosine triphosphate) molecules. When P-gp is in an inward-facing conformation, substrates enter a binding cavity from the cell’s cytoplasm or inner membrane. Upon substrate binding, ATP molecules attach, leading to a conformational change that shifts the substrate for expulsion. The hydrolysis of ATP facilitates substrate expulsion and resets the pump for another cycle. This process allows P-gp to efficiently remove various compounds, including drugs, steroids, lipids, and other xenobiotics, from inside the cell.
P-gp’s Role in Drug Movement in the Body
P-gp significantly influences the pharmacokinetics of many drugs, affecting how they are absorbed, distributed, and eliminated within the body. This transporter acts as a biological barrier, extruding toxins and foreign substances out of cells. Its widespread presence in various organs directly impacts the bioavailability and tissue concentrations of medications.
In the intestines, P-gp is highly expressed on the apical surface of enterocytes, which are cells lining the gut. When oral medications are taken, P-gp can pump these drugs back into the intestinal lumen, effectively reducing the amount that enters the bloodstream and lowering their oral absorption. For instance, the oral bioavailability of digoxin, a common P-gp substrate, can be reduced by approximately 30% due to this efflux mechanism.
P-gp also plays a significant role at the blood-brain barrier, where it limits the entry of many drugs into the brain. This protective function prevents potentially harmful substances from reaching the central nervous system. For example, loperamide, an opioid drug, primarily exerts its antidiarrheal effects peripherally because P-gp actively pumps it out of the brain, preventing central nervous system side effects.
Beyond absorption and distribution, P-gp contributes to drug elimination in the liver and kidneys. In liver cells, P-gp actively transports drugs into bile ducts, facilitating their removal from the body. Similarly, in the kidneys, P-gp moves drugs from the cells of the proximal tubules into the urine for excretion. This combined action across multiple organs underscores P-gp’s broad impact on the overall movement and fate of drugs in the body.
Practical Importance of P-gp Substrates
P-gp activity affects drug efficacy, contributes to drug resistance, and leads to drug-drug interactions. When P-gp actively pumps a drug out of target cells or tissues, it can reduce the drug’s concentration at its intended site of action, diminishing its effectiveness. This is particularly relevant for drugs that need to reach specific organs, such as the brain, where P-gp acts as a barrier.
P-gp overexpression contributes to multidrug resistance, especially in cancer chemotherapy. Cancer cells can produce increased amounts of P-gp, which then pumps chemotherapeutic agents out of the tumor cells before they can exert their cytotoxic effects. This efflux mechanism keeps drug concentrations below the therapeutic threshold, rendering cancer cells resistant to various anti-cancer treatments. Researchers are investigating strategies to overcome this resistance by influencing P-gp levels.
Drug-drug interactions result from P-gp’s activity. The pharmacokinetics of a P-gp substrate drug can be altered when co-administered with substances that either inhibit or induce P-gp’s function. P-gp inhibitors, such as verapamil or clarithromycin, can block the pump’s activity, leading to higher levels of P-gp substrate drugs in the body. This increase can result in enhanced therapeutic effects but also a greater risk of side effects or toxicity.
Conversely, P-gp inducers, like rifampicin or St. John’s Wort, can increase the expression or activity of P-gp, causing the pump to remove P-gp substrate drugs more rapidly. This increased efflux can lead to lower drug concentrations in the body, potentially reducing the drug’s effectiveness. For example, co-administration of rifampicin with digoxin can decrease digoxin levels due to increased P-gp activity. Understanding these interactions is important for healthcare professionals to manage drug regimens and ensure patient safety and optimal treatment outcomes.