What are the examples of P-gp inhibitors? A Comprehensive Guide

October 13, 2025 •

3 min read

P-glycoprotein (P-gp) is responsible for a major mechanism of chemotherapy resistance, a phenomenon that can severely hinder the effectiveness of cancer treatment. As such, understanding and inhibiting this efflux pump has become a key strategy in pharmacology. Numerous medications and natural products, often categorized into generations, serve as examples of P-gp inhibitors.

Quick Summary

P-gp inhibitors are substances that block the cellular efflux pump, P-glycoprotein, to increase the intracellular concentration of other drugs. Common examples include calcium channel blockers, some antibiotics, and antifungals. This can lead to significant drug interactions.

Key Points

Diverse Drug Classes: Examples of P-gp inhibitors are found across numerous drug classes, including calcium channel blockers, antibiotics, antifungals, and HIV protease inhibitors.
Generational Development: Inhibitors have evolved from less specific, more toxic first-generation agents like verapamil to highly selective third-generation compounds such as tariquidar.
Enhance Drug Bioavailability: By blocking the P-gp efflux pump, inhibitors increase the intracellular concentration and systemic exposure of co-administered substrate drugs.
Significant Drug Interactions: The potent inhibition of P-gp can lead to clinically significant and sometimes dangerous drug-drug interactions, requiring careful monitoring.
Overcoming Multidrug Resistance: A primary application of P-gp inhibitors is to counteract the efflux mechanism that leads to multidrug resistance in cancer cells.
Affects Specific Drug Substrates: Notable P-gp substrate drugs affected by inhibitors include the cardiac medication digoxin and the anticoagulant dabigatran.
Natural Sources: Certain natural products, including furanocoumarins from grapefruit juice and various flavonoids, also act as P-gp inhibitors.

Understanding P-gp and the Need for Inhibitors

P-glycoprotein, also known as multidrug resistance protein 1 (MDR1) or ABCB1, is an ATP-dependent drug efflux pump widely distributed throughout the body. Located in the membranes of cells in the intestines, liver, kidneys, and at the blood-brain barrier, its primary function is to pump foreign substances, or xenobiotics, out of cells. This protective mechanism, while vital for detoxification, can severely reduce the bioavailability and efficacy of many therapeutic agents, leading to multidrug resistance (MDR).

The pharmacological goal of P-gp inhibitors is to counteract this efflux activity, thereby increasing the intracellular concentration of co-administered drugs. Inhibitors can work through several mechanisms: by blocking the drug-binding site, interfering with ATP hydrolysis, or altering the integrity of the cell membrane. The clinical significance of P-gp inhibition is most notable in oncology, where it can sensitize cancer cells to chemotherapeutic drugs, and in managing drug-drug interactions where a medication's systemic exposure needs to be carefully controlled.

Generations of P-gp Inhibitors

Efforts to develop P-gp inhibitors led to a classification based on their characteristics.

First-Generation Inhibitors

These early inhibitors, like verapamil, cyclosporine A, and quinidine, had low specificity and dose-limiting side effects.

Second-Generation Inhibitors

Designed with improved specificity, examples like valspodar (PSC 833) still faced challenges with interactions with other enzymes like CYP3A4.

Third-Generation Inhibitors

Representing the most selective and potent inhibitors, this generation includes elacridar (GF120918), zosuquidar (LY335979), and tariquidar (XR9576). Despite their promise, clinical success in overcoming cancer MDR has been limited.

Examples of P-gp Inhibitors by Therapeutic Class

Many clinically used drugs across different therapeutic classes are known to inhibit P-gp, impacting drug interactions.

Antibiotics: Macrolides such as clarithromycin and erythromycin are potent inhibitors.
Antifungals: Azoles like ketoconazole and itraconazole strongly inhibit P-gp and CYP3A4.
Cardiovascular Agents: Examples include amiodarone, carvedilol, and ticagrelor. Caution is needed with drugs like digoxin, which is a P-gp substrate.
HIV Protease Inhibitors: Ritonavir and saquinavir are both substrates and inhibitors. Ritonavir is often used to boost levels of other HIV drugs.
Herbal Products: Compounds in grapefruit juice like bergamottin can inhibit P-gp.

P-gp Inhibitors vs. P-gp Substrates

P-gp inhibitors block the efflux pump, while P-gp substrates are transported by it. Some drugs can be both. Inhibitors increase the bioavailability of substrates, potentially causing toxicity.


Feature	P-gp Inhibitors	P-gp Substrates
Function	Block the P-gp efflux pump.	Are transported out of cells by the P-gp pump.
Effect on Other Drugs	Increase bioavailability and systemic concentration of co-administered P-gp substrates.	Are affected by P-gp inhibitors, which can raise their own levels.
Drug Examples	Verapamil, Ketoconazole, Clarithromycin, Ritonavir.	Digoxin, Dabigatran, Colchicine, Tacrolimus.
Clinical Consequence	Risk of toxicity for co-administered P-gp substrates.	Reduced bioavailability and efficacy, risk of inadequate therapeutic levels.

The Role of P-gp Inhibitors in Drug Interactions

P-gp inhibitors have significant clinical impact on drug interactions. For instance, co-administering the blood thinner dabigatran (a substrate) with ketoconazole (a potent inhibitor) can increase bleeding risk. Similarly, quinidine (an inhibitor) with loperamide (a substrate) can allow loperamide to cross the blood-brain barrier. Careful management of these interactions is vital.

Conclusion

P-gp inhibitors are crucial in pharmacology for modulating the P-glycoprotein efflux pump. They are found in many drug classes and natural products and are important for managing drug interactions and combating resistance. Continued research aims to develop more specific agents to improve therapeutic outcomes.

Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibitory Activities in Cancer Treatment

Frequently Asked Questions

Understanding P-gp inhibitors is crucial because they can cause significant drug-drug interactions. By blocking P-gp, they increase the concentration of other medications in the body, which can lead to enhanced therapeutic effects or, more dangerously, increased toxicity.

A drug that is both a P-gp substrate and an inhibitor, like ritonavir, can lead to complex pharmacokinetic interactions. The inhibitory effect can increase its own plasma levels and those of other co-administered P-gp substrates, while its function as a substrate influences its distribution and elimination.

P-gp inhibitors function by interfering with the P-glycoprotein efflux pump, which normally uses ATP to expel foreign substances from cells. They can achieve this by blocking the drug-binding site, inhibiting the pump's ATPase activity, or altering the cell membrane's structure.

Yes, several natural products have been identified as P-gp inhibitors. A prominent example includes the furanocoumarins found in grapefruit juice, which can increase the bioavailability of certain medications. Flavonoids and other plant-derived compounds also have inhibitory effects.

First-generation inhibitors are older drugs repurposed for P-gp inhibition but suffer from low specificity and high toxicity. Second-generation inhibitors are more selective but still interact with other systems. Third-generation inhibitors, like tariquidar, are highly specific but have shown limited success in clinical cancer trials.

P-gp is present at the blood-brain barrier, where it limits the entry of many drugs into the brain. Co-administering a P-gp inhibitor with a P-gp substrate drug can increase the brain's exposure to that drug, potentially leading to central nervous system side effects.

Clinicians should be aware of many P-gp inhibitors, particularly strong ones like ketoconazole, clarithromycin, and ritonavir, as well as commonly used agents like verapamil. They must consider potential interactions with key P-gp substrates such as dabigatran, digoxin, and tacrolimus to prevent adverse events.