What Interferes with Phenytoin Absorption? Critical Factors and Interactions

October 9, 2025 •

4 min read

Phenytoin absorption can be substantially reduced by up to 70% when the oral suspension is co-administered with enteral feedings. Understanding what interferes with phenytoin absorption is crucial for patients and healthcare providers to maintain stable therapeutic drug levels and ensure effective seizure control.

Quick Summary

Several factors can decrease the absorption of phenytoin, including concurrent use of antacids containing aluminum, calcium, and magnesium; administration via enteral feeding tubes, particularly with the suspension; and the consumption of high-protein meals. St. John's wort and certain dietary supplements can also impact its effectiveness.

Key Points

Antacids are major culprits: Antacids containing aluminum, calcium, or magnesium can bind to phenytoin, severely limiting its absorption.
Enteral feeding is a significant factor: For patients with feeding tubes, concurrent administration, especially of the suspension, dramatically reduces phenytoin absorption.
Stagger administration times: To counter absorption issues with antacids, sucralfate, and enteral feeding, separating doses by a couple of hours is the primary management strategy.
Protein intake can interfere: High-protein meals can reduce the bioavailability of phenytoin, potentially impacting drug levels.
Formulation matters with food: The specific formulation (capsule vs. suspension) can influence how food affects phenytoin absorption, with some capsules potentially better absorbed with meals.
Herbal supplements pose risks: St. John's wort is a notable herbal that can significantly decrease phenytoin levels and should be avoided.
Close monitoring is essential: Due to phenytoin's narrow therapeutic window, monitoring serum levels is critical whenever changes are made to a patient's medication, diet, or feeding regimen.

The Importance of Consistent Phenytoin Levels

Phenytoin is a narrow therapeutic index drug, meaning the range between an effective dose and a toxic dose is very small. Maintaining a consistent serum concentration is therefore critical for managing seizures and preventing adverse effects. A reduction in absorption can lead to sub-therapeutic levels, increasing the risk of breakthrough seizures. Conversely, an unexpected increase in absorption can lead to toxicity, causing symptoms like nystagmus, ataxia, and lethargy.

Medications and Supplements That Block Phenytoin Absorption

Antacids and Gastric-Protective Agents

Antacids are commonly used to treat indigestion and heartburn, but many contain minerals that can bind with phenytoin, effectively preventing its absorption.

Calcium, Magnesium, and Aluminum: These mineral ions, found in popular antacid brands like Tums and Maalox, form insoluble complexes with phenytoin in the gastrointestinal tract, leading to decreased bioavailability. To minimize this interaction, experts recommend separating the administration of phenytoin and antacids by at least two to three hours.
Sucralfate: This medication, used to treat ulcers, works by forming a protective coating over the stomach lining. Studies have shown that it can reduce phenytoin absorption by 20-30%. Like antacids, separating the doses by a couple of hours can help mitigate this effect.

Herbal and Dietary Supplements

Some over-the-counter supplements can interfere with phenytoin absorption and metabolism, posing a risk to seizure control.

St. John's Wort: This herbal supplement is a potent enzyme inducer that can decrease the amount of phenytoin in the blood, reducing its effectiveness. It should not be taken concurrently with phenytoin.
High-Dose Folic Acid: While phenytoin can cause folate deficiency, taking high doses of folic acid supplements may accelerate the elimination of phenytoin from the body, making it less effective.
Calcium and Vitamin D: While supplementation may be necessary for long-term phenytoin users due to its effects on bone health, calcium supplements should be taken hours apart from phenytoin to avoid absorption interference.

The Significant Impact of Enteral Feeding

For patients who receive nutrition via a feeding tube, especially those in critical care settings, managing phenytoin absorption is a significant challenge.

Mechanisms of Interference

Physical Adsorption: Phenytoin, particularly the suspension formula, has a tendency to adhere to the polyvinyl chloride (PVC) material of nasogastric (NG) feeding tubes. This can trap the drug, preventing it from reaching the small intestine for absorption.
Formula Interaction: Components within the enteral feeding formula itself can interact with phenytoin. Studies suggest that certain proteins, like those derived from soy and casein, play a role in reducing the drug's bioavailability.
Severity of Reduction: The absorption reduction can be substantial, with reported decreases in serum phenytoin levels of up to 75% when given with continuous tube feedings.

Management Strategies for Enteral Feeding

Staggering Doses: The most common and effective strategy is to interrupt the enteral feeding for a period around phenytoin administration. Recommendations often include stopping the feed for one to two hours before and after the phenytoin dose.
Flushing the Tube: Flushing the feeding tube with water before and after administering the phenytoin dose can help minimize drug loss due to tube adhesion.
Monitoring Levels: Regular monitoring of serum phenytoin levels is essential when a patient starts or stops enteral feeding to ensure therapeutic concentrations are maintained.

Dietary and Food Interactions

Beyond enteral formulas, specific dietary patterns can also influence phenytoin absorption.

High-Protein Meals: Some research indicates that high-protein intake can reduce phenytoin absorption, while carbohydrates may have an enhancing effect. To promote consistent absorption, healthcare providers might advise taking phenytoin with or after food, but avoiding exceptionally high-protein meals at the same time.
Different Formulations: The interaction with food can vary depending on the phenytoin formulation. For instance, some studies have noted better absorption of certain capsule types when taken with food.

Potential Complications of Altered Absorption

Loss of Seizure Control: Inconsistent or reduced absorption can lead to sub-therapeutic phenytoin levels, increasing the frequency and severity of seizures, as seen in reported cases.
Unpredictable Toxicity: Conversely, if a factor that was hindering absorption is removed (e.g., stopping enteral feeding), a patient's phenytoin levels could rise sharply, leading to toxicity. Careful monitoring is essential during any change.
Long-Term Health Risks: Chronic issues with phenytoin absorption can affect other health aspects, such as exacerbating nutritional deficiencies related to folate and vitamin D.

Comparison of Common Phenytoin Absorption Interferences


Interfering Factor	Mechanism of Interference	Impact on Phenytoin Absorption	Recommended Management Strategy
Enteral Feeding	Adsorption to feeding tube materials (especially suspension) and physical interaction with formula components (e.g., protein).	Significant reduction (up to 75%).	Stagger administration (1-2 hours before and after), flush tube with water, and monitor serum levels.
Antacids (Ca, Mg, Al)	Mineral ions bind with phenytoin in the GI tract, forming insoluble compounds.	Significant reduction.	Separate administration by at least two to three hours.
Sucralfate	Forms a protective coating in the stomach that can entrap phenytoin.	Moderate reduction (20-30%).	Separate administration by at least two hours.
High-Protein Meals	May reduce the drug's bioavailability, though the effect can vary.	Moderate reduction.	Take phenytoin with or after food, but avoid taking it alongside excessively high-protein meals.
St. John's Wort	Induces liver enzymes that increase phenytoin metabolism, lowering blood concentration.	Significant reduction in drug effectiveness (metabolic, not absorptive).	Avoid use entirely while on phenytoin.

Conclusion: Ensuring Effective Phenytoin Therapy

For patients on phenytoin, understanding what interferes with phenytoin absorption is paramount. The drug's narrow therapeutic index means that even small changes in bioavailability can have significant clinical consequences. Enteral tube feeding, antacids containing calcium, magnesium, or aluminum, and the ulcer medication sucralfate are major culprits that can directly reduce absorption. Furthermore, dietary components like high protein meals and certain supplements like St. John's wort can also compromise drug levels. Close collaboration with healthcare providers is essential to create an effective administration schedule and to carefully monitor serum phenytoin levels, especially when starting or stopping interacting substances. This proactive approach helps ensure stable seizure control and minimizes the risk of toxicity.

Frequently Asked Questions

No, it is recommended that you take antacids at least two to three hours before or after your phenytoin dose. Antacids containing minerals like calcium, aluminum, or magnesium can bind to phenytoin and decrease its absorption.

Enteral feeding can significantly decrease phenytoin absorption, especially with the oral suspension. This is because the drug can adhere to the feeding tube and interact with components in the formula. Staggering doses by a couple of hours and flushing the tube is often necessary.

You may need to make adjustments. Consistent intake is key, as high-protein meals have been shown to reduce absorption. Talk to your doctor about how to best coordinate your medication with your meals.

Sucralfate, an ulcer medication, can reduce phenytoin absorption by 20-30%. To prevent this interaction, separate the administration of the two medications by at least two hours.

It is generally advised to avoid herbal supplements with phenytoin unless approved by your doctor. St. John's wort, for example, is known to significantly reduce phenytoin blood levels.

Phenytoin has a narrow therapeutic index, meaning its effective dose is very close to its toxic dose. Inconsistent absorption can lead to drug levels that are too low to prevent seizures or too high and cause toxicity.

If you are on enteral feeding, your doctor will likely prescribe a regimen that includes staggering the phenytoin dose. When you stop enteral feeding, your phenytoin levels may increase, so your doctor will need to monitor your serum levels and potentially adjust your dosage.