Which drugs inhibit P-glycoprotein? A Comprehensive Guide

Overexpression of P-glycoprotein (P-gp) in cancer cells is a primary cause of multidrug resistance, a major hurdle in chemotherapy. Understanding which drugs inhibit P-glycoprotein is crucial for optimizing drug efficacy, overcoming resistance, and preventing adverse drug interactions.

Quick Summary

P-glycoprotein (P-gp) inhibitors are substances that block the P-gp efflux pump, increasing intracellular drug concentrations. This guide details key inhibitors, their mechanisms, and clinical importance in drug therapy and overcoming resistance.

Key Points

• What is P-gp?: P-glycoprotein (P-gp/MDR1) is an efflux pump in cell membranes that removes drugs and toxins, affecting their absorption and distribution.

• Inhibition Increases Drug Levels: P-gp inhibitors block this pump, leading to higher intracellular concentrations of other drugs (substrates), which can cause toxicity.

• Key Inhibitors: Common inhibitors include certain antibiotics (clarithromycin), antifungals (ketoconazole), cardiovascular drugs (verapamil, amiodarone), and HIV medications (ritonavir).

• Overcoming Cancer Resistance: Inhibiting P-gp is a key strategy to fight multidrug resistance in cancer, as it stops cancer cells from pumping out chemotherapy drugs.

• Blood-Brain Barrier: P-gp acts as a gatekeeper at the blood-brain barrier; inhibitors can increase drug penetration into the brain.

• Natural Inhibitors: Compounds in grapefruit juice, curcumin (turmeric), and quercetin can inhibit P-gp, leading to food-drug interactions.

• Inhibitors vs. Inducers: While inhibitors increase drug levels, inducers (like St. John's Wort and Rifampin) decrease them, potentially causing treatment failure.

Understanding P-glycoprotein (P-gp)

P-glycoprotein (P-gp), also known as Multidrug Resistance Protein 1 (MDR1) or ABCB1, is an important protein pump in cell membranes that transports a variety of substances out of cells. This pump, encoded by the ABCB1 gene, is an ATP-dependent efflux pump that acts as a defense mechanism by expelling toxins and foreign substances from the body.

P-gp is found in key locations throughout the body where it plays a role in barrier and excretory functions:

• Intestinal Epithelium: Reduces drug absorption by pumping drugs back into the intestine.
• Liver and Kidney: Helps eliminate drugs and their metabolites in bile and urine.
• Blood-Brain Barrier (BBB): Limits the entry of many drugs into the central nervous system.
• Other Tissues: Also present in areas like the placenta and testes.

The Role of P-gp Inhibition

Inhibiting P-gp means blocking this pump, which increases the levels of drugs that are P-gp substrates. This has several clinical implications:

• Increased Drug Bioavailability: More drug can be absorbed from the gut.
• Enhanced Drug Delivery: More drugs can potentially enter the brain by inhibiting P-gp at the BBB.
• Overcoming Multidrug Resistance (MDR): In cancer treatment, inhibiting P-gp can help chemotherapy drugs stay inside cancer cells that are resistant due to P-gp overexpression.
• Drug-Drug Interactions (DDIs): Inhibiting P-gp can cause dangerous interactions by raising substrate drug levels to toxic concentrations. For instance, certain heart medications can increase levels of digoxin, a P-gp substrate.

Comprehensive List of P-glycoprotein Inhibitors

P-gp inhibitors come from many different drug classes and sources, varying in their strength of inhibition.

Synthetic and Prescription Drug Inhibitors

Many common medications can inhibit P-gp:

• Cardiovascular Drugs: Amiodarone, carvedilol, dronedarone, propafenone, quinidine, ranolazine, ticagrelor, and verapamil.
• Antibiotics and Antifungals: Clarithromycin, erythromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
• HIV Protease Inhibitors: Ritonavir, nelfinavir, and saquinavir.
• Immunosuppressants: Cyclosporine and tacrolimus.
• Other Inhibitors: Elacridar, Tariquidar, Zosuquidar, Lapatinib, and Tamoxifen.

Natural P-gp Inhibitors

Certain natural compounds, found in foods and supplements, can also inhibit P-gp:

• Flavonoids and Polyphenols: Quercetin, wogonin, grape seed procyanidin, and curcumin.
• Terpenoids: Limonin, lupeol, and phytol.
• Alkaloids: Berbamine, reserpine, and lobeline.
• Other Sources: Garlic supplements and grapefruit juice (due to furanocoumarins).

Comparison Table: P-gp Inhibitors vs. Inducers

Feature	P-gp Inhibitors	P-gp Inducers
Primary Effect	Block the P-gp pump, preventing it from expelling substrates.	Increase the number or activity of P-gp pumps.
Impact on Substrate	Increase intracellular and plasma concentrations of co-administered P-gp substrates.	Decrease intracellular and plasma concentrations of co-administered P-gp substrates.
Clinical Consequence	Can lead to increased drug efficacy, overcoming resistance, or causing toxicity.	Can lead to therapeutic failure due to inadequate drug levels.
Examples	Verapamil, Clarithromycin, Ritonavir, Ketoconazole, Cyclosporine, Quercetin, Curcumin.	Rifampin, St. John's Wort, Carbamazepine, Phenytoin, Phenobarbital.

Conclusion

P-glycoprotein is a crucial protein influencing how the body handles many medications. Inhibiting P-gp can increase drug levels, offering therapeutic benefits in overcoming cancer resistance and improving drug delivery to the brain. However, this can also lead to significant and potentially dangerous drug interactions. Healthcare professionals need to be aware of which drugs inhibit P-gp to ensure patient safety and optimize treatment outcomes.

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For more information on P-gp and its role in drug interactions, a valuable resource is the U.S. Food and Drug Administration (FDA) table on drug transporters.

Frequently Asked Questions

What is P-glycoprotein (P-gp)?

P-glycoprotein (P-gp), also known as MDR1, is an ATP-dependent efflux pump protein found in cell membranes. Its primary role is to transport a wide variety of foreign substances, including many drugs and toxins, out of cells, thus limiting their absorption and efficacy.

Why is P-gp inhibition clinically important?

P-gp inhibition is clinically significant because it can increase a drug's concentration in the body, potentially leading to toxicity. However, it can also be used therapeutically to overcome multidrug resistance in cancer and to enhance the delivery of drugs across the blood-brain barrier.

What happens when a P-gp inhibitor and a P-gp substrate are taken together?

When a P-gp inhibitor is taken with a P-gp substrate (a drug that is pumped by P-gp), the inhibitor blocks the pump. This causes the substrate's concentration to increase, sometimes to dangerous levels. For example, taking the inhibitor verapamil can increase levels of the substrate digoxin.

Can food inhibit P-glycoprotein?

Yes, certain natural compounds found in food can inhibit P-gp. Notable examples include furanocoumarins in grapefruit juice, curcumin in turmeric, and flavonoids like quercetin found in various fruits and vegetables.

What is the difference between a P-gp inhibitor and a P-gp inducer?

A P-gp inhibitor blocks the pump's action, leading to increased drug concentrations. In contrast, a P-gp inducer (like St. John's wort or rifampin) increases the number or activity of P-gp pumps, leading to decreased drug concentrations and potential therapeutic failure.

Name some strong P-gp inhibitors.

Some strong P-gp inhibitors include the antifungal drugs itraconazole and ketoconazole, the antibiotic clarithromycin, and the HIV protease inhibitor ritonavir.

How does P-gp affect drugs getting into the brain?

P-gp is highly expressed at the blood-brain barrier, where it functions as a gatekeeper, pumping many drugs out and preventing them from entering the central nervous system. Inhibiting P-gp is a strategy being explored to allow therapeutic drugs to better penetrate the brain.