What drugs are inhibitors of cytochrome P450?

October 14, 2025 •

4 min read

Over 50 distinct cytochrome P450 (CYP450) enzymes have been identified, with six of them metabolizing 90% of drugs [1.5.3]. Understanding what drugs are inhibitors of cytochrome P450 is crucial for preventing dangerous drug-drug interactions and ensuring medication safety and efficacy.

Quick Summary

A detailed overview of cytochrome P450 enzyme inhibitors, including their mechanisms, clinical significance, and specific drug examples, categorized by the CYP enzyme they affect and their strength of inhibition.

Key Points

Central Role in Metabolism: Six key cytochrome P450 (CYP450) enzymes metabolize about 90% of all drugs, with CYP3A4 being the most prominent [1.5.3, 1.7.1].
Inhibition Leads to Risk: CYP inhibitors block enzyme activity, causing other drugs (substrates) to accumulate in the body, which can lead to toxicity [1.5.5].
Mechanisms Vary: Inhibition can be reversible (competitive or non-competitive) or irreversible, impacting the duration and management of the interaction [1.4.1, 1.4.2].
Strength Matters: Inhibitors are classified as strong, moderate, or weak, which helps predict the clinical significance of a potential drug interaction [1.9.1].
Common Drug Classes: Many common medications, including certain antidepressants (fluoxetine), antibiotics (clarithromycin), and antifungals (ketoconazole), are potent inhibitors [1.7.1, 1.8.1].
Natural Inhibitors Exist: Foods like grapefruit juice and herbal supplements like St. John's wort can cause significant CYP450-mediated drug interactions [1.2.3, 1.6.3].
High Clinical Prevalence: The risk of a CYP-mediated drug interaction increases dramatically with the number of medications a person takes [1.3.1].

The Critical Role of Cytochrome P450 Enzymes

Cytochrome P450 (CYP450) enzymes are a superfamily of proteins essential for the metabolism of a vast number of substances, including a majority of clinically used drugs [1.5.3, 1.5.4]. These enzymes, located primarily in the liver but also in the small intestine, kidneys, and lungs, play a central role in Phase I drug metabolism [1.5.3, 1.5.5]. Their primary function is to convert lipid-soluble compounds into more water-soluble forms, facilitating their excretion from the body [1.5.5]. The six main enzymes responsible for the bulk of drug metabolism are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 [1.5.3]. Given that over 50% of medications are metabolized by CYP3A4 alone, any interference with this system can have profound clinical consequences [1.7.1].

Mechanisms of CYP450 Inhibition

CYP450 inhibition occurs when a substance, known as an inhibitor, blocks the metabolic activity of one or more of these enzymes [1.5.3]. This leads to a decreased rate of metabolism for other drugs (substrates) that rely on the same enzyme, causing their plasma concentrations to rise, which can result in toxicity or adverse effects [1.5.5]. Inhibition can be classified into several types:

Reversible Inhibition

This is a temporary form of inhibition that can be categorized further:

Competitive Inhibition: This is the most common mechanism, where the inhibitor competes with the substrate for the same active site on the enzyme. The outcome depends on the drug with the higher concentration or stronger affinity for the site [1.4.1, 1.4.3]. Its effects are immediate and can be mitigated by separating the administration times of the competing drugs [1.4.1].
Non-competitive Inhibition: The inhibitor binds to an allosteric (different) site on the enzyme, changing its shape and preventing the substrate from binding. This type of inhibition is not overcome by increasing the substrate concentration and is long-lasting [1.4.1, 1.4.3].
Mixed Inhibition: This involves the inhibitor binding to both the active site and an allosteric site. These are often very potent inhibitors, such as the antifungal drug ketoconazole [1.4.1].

Irreversible Inhibition

Also known as mechanism-based inhibition, this occurs when an inhibitor permanently binds to and deactivates the enzyme. Enzyme activity only returns to normal after the body synthesizes new enzymes, a process that can take several days [1.4.2].

Clinical Significance and Consequences

The prevalence of potential CYP-mediated drug-drug interactions (DDIs) is high, especially in older adults with polypharmacy. One study found that for patients taking 5-9 drugs, the probability of at least one CYP-mediated DDI was 50%, rising to 100% for those taking 20 or more drugs [1.3.1]. Such interactions can lead to serious outcomes:

Increased Drug Toxicity: When an inhibitor slows the metabolism of another drug, the latter can accumulate to toxic levels. For example, combining the CYP2C9 inhibitor miconazole with the anticoagulant warfarin can lead to a dangerously high INR and increased risk of bleeding [1.5.4].
Therapeutic Failure: In the case of prodrugs, which must be metabolized into their active form, inhibition can prevent this activation. For instance, codeine is converted to its active form, morphine, by CYP2D6. A CYP2D6 inhibitor can block this conversion, leading to a lack of pain relief [1.2.3].
Market Withdrawals: Historically, severe DDIs mediated by CYP inhibition have led to drugs like terfenadine (Seldane) and mibefradil (Posicor) being withdrawn from the market due to life-threatening adverse events when combined with inhibitors [1.5.3].

Common CYP450 Inhibitors by Enzyme

Drugs are often classified as strong, moderate, or weak inhibitors based on their potential to increase the plasma concentration (AUC) of sensitive substrates [1.9.1].

CYP3A4 Inhibitors

CYP3A4 is involved in the metabolism of over half of all drugs [1.7.1].

Strong Inhibitors: Antifungals (ketoconazole, itraconazole), some antibiotics (clarithromycin), and protease inhibitors used for HIV (ritonavir, indinavir) [1.7.1, 1.8.1].
Moderate Inhibitors: Diltiazem, verapamil, erythromycin, and fluconazole [1.7.1, 1.8.1].
Weak Inhibitors: Cimetidine [1.7.1].

CYP2D6 Inhibitors

Strong Inhibitors: Antidepressants like bupropion, fluoxetine, and paroxetine, as well as the cardiac drug quinidine [1.8.1, 1.8.2].
Moderate Inhibitors: Duloxetine, sertraline, and terbinafine [1.8.1, 1.8.2].
Weak Inhibitors: Cimetidine, diphenhydramine (Benadryl), and risperidone [1.2.3, 1.2.5].

CYP2C19 Inhibitors

Strong Inhibitors: The antidepressant fluvoxamine and the antifungal fluconazole [1.9.1, 1.9.2].
Moderate Inhibitors: Proton pump inhibitors like omeprazole and esomeprazole [1.2.4, 1.9.1].
Weak Inhibitors: Cimetidine, clopidogrel, and garlic supplements [1.9.1].

CYP1A2 Inhibitors

Strong Inhibitors: Fluvoxamine, ciprofloxacin, and enoxacin [1.10.1, 1.10.2].
Moderate Inhibitors: Caffeine and mexiletine [1.10.1].
Weak Inhibitors: Cimetidine and acyclovir [1.10.1].

Natural and Food-Based Inhibitors

It is not just prescription drugs that inhibit CYP450 enzymes. Several common foods and herbal supplements can cause clinically significant interactions.

Grapefruit Juice: A well-known potent inhibitor of intestinal CYP3A4, it can dramatically increase the levels of drugs like statins and some calcium channel blockers [1.2.3, 1.6.3].
St. John's Wort: While primarily known as an inducer, it can also have inhibitory effects on some enzymes [1.6.1, 1.6.3].
Other Substances: Turmeric (curcumin), peppermint, German chamomile, and Goldenseal have all been shown to have CYP inhibitory properties [1.6.1, 1.6.2, 1.6.3].

Inhibitor Strength Comparison Table


Inhibitor Strength	Effect on Substrate AUC*	Clinical Consideration	Example Inhibitor (Enzyme)
Strong	≥5-fold increase	Co-administration is often contraindicated or requires significant dose adjustment.	Ritonavir (CYP3A4) [1.7.1]
Moderate	≥2- to <5-fold increase	Requires close monitoring and possible dose adjustments. Interaction potential is high.	Fluconazole (CYP3A4) [1.7.1, 1.8.1]
Weak	≥1.25- to <2-fold increase	Clinically significant interactions are less common but possible, especially with narrow therapeutic index drugs.	Cimetidine (CYP3A4) [1.7.1]

AUC (Area Under the Curve) refers to the total drug exposure over time [1.9.1].

Conclusion

Understanding which drugs, foods, and supplements act as inhibitors of cytochrome P450 enzymes is a cornerstone of safe prescribing and patient care. Inhibition of these metabolic pathways can lead to a cascade of effects, from reduced drug efficacy to life-threatening toxicity. Healthcare professionals must remain vigilant, utilizing resources like drug interaction tables and considering a patient's entire regimen—including over-the-counter products and herbal supplements—to anticipate and mitigate the risks associated with CYP450 inhibition. As polypharmacy becomes more common, this knowledge is more critical than ever to ensure patient safety [1.3.1].

For a comprehensive and regularly updated list of drug interactions, consult an authoritative resource such as the FDA's Drug Development and Drug Interactions Table [1.2.1].

Frequently Asked Questions

The CYP3A4 enzyme is the most common and is responsible for the metabolism of more than 50% of clinically used medications [1.5.3, 1.7.1].

Strong inhibitors of CYP3A4 include protease inhibitors like ritonavir, macrolide antibiotics like clarithromycin, and azole antifungals like ketoconazole and itraconazole [1.7.1, 1.8.1].

Grapefruit juice is a potent inhibitor of the CYP3A4 enzyme located in the small intestine. This inhibition reduces the first-pass metabolism of many drugs, leading to significantly higher concentrations in the bloodstream [1.2.3, 1.6.5].

A CYP inhibitor blocks or slows down enzyme activity, leading to increased levels of other drugs. A CYP inducer speeds up enzyme activity, which increases drug metabolism and can lead to decreased drug levels and therapeutic failure [1.5.3, 1.5.5].

Yes, several antidepressants are potent inhibitors. For example, fluoxetine (Prozac) and paroxetine (Paxil) are strong inhibitors of CYP2D6, and fluvoxamine (Luvox) is a strong inhibitor of CYP1A2 and CYP2C19 [1.8.3, 1.10.1].

A prodrug needs to be metabolized by a CYP enzyme to become active. If that enzyme is inhibited, the prodrug cannot be converted to its active form, which can result in therapeutic failure. An example is codeine, which requires CYP2D6 to be converted to morphine [1.2.3, 1.4.1].

Not always, but they are always a risk that needs to be managed. While many interactions can lead to dangerous toxicity, some are intentionally used in medicine (e.g., ritonavir to 'boost' levels of other HIV drugs). The clinical significance depends on the specific drugs, their doses, and the patient [1.5.3, 1.6.5].