The Pharmacological Mechanism of the Interaction
To understand the interaction between quercetin and losartan, it is essential to first understand how each substance is processed by the body. Losartan is an angiotensin II receptor blocker (ARB) used to treat high blood pressure, and it requires conversion into a more potent form to work effectively. Quercetin, a common dietary supplement, can interfere with this process.
Losartan's Metabolism and Action
Losartan undergoes extensive first-pass metabolism in the liver, primarily by the cytochrome P450 (CYP) enzymes CYP2C9 and CYP3A4. This process converts losartan into a more potent 5-carboxylic acid metabolite, often referred to as EXP3174. This metabolite is responsible for a significant portion of losartan's blood pressure-lowering effect, and its concentration in the body is directly linked to the drug's efficacy.
Quercetin's Inhibitory Effects on Enzymes and Transporters
Quercetin is known to inhibit multiple CYP enzymes, including CYP2C9 and CYP3A4. By blocking these enzymes, quercetin can hinder the normal metabolism of other drugs, such as losartan. The inhibition of CYP2C9, in particular, is a key concern, as it directly reduces the formation of the active EXP3174 metabolite.
Furthermore, research indicates that quercetin can inhibit P-glycoprotein (P-gp), an efflux transporter protein found in the intestines and other tissues. P-gp functions as a pump, moving drugs from inside cells back out. By inhibiting P-gp, quercetin can increase the absorption and systemic concentration of co-administered drugs.
Findings from Animal and In Vitro Studies
Preclinical studies, primarily conducted in rats, provide the most direct evidence of the quercetin-losartan interaction. A 2019 study published in Pharmacological Reports investigated the effects of quercetin pretreatment on the pharmacokinetics of losartan in rats. The results were significant:
- Pretreatment with quercetin led to a notable increase in the maximum plasma concentration ($C_{max}$) and the area under the curve (AUC) of losartan.
- The same pretreatment resulted in a significant decrease in the plasma concentration of the active metabolite, EXP3174.
- The half-life ($t_{1/2}$) of losartan was prolonged, indicating it stayed in the system longer.
- The study concluded that quercetin likely increases losartan absorption by inhibiting P-gp and decreases its metabolic breakdown by inhibiting CYP450 enzymes.
Potential Clinical Risks and Considerations
While the above findings are based on animal and in vitro studies, they highlight potential risks that could translate to humans. The interaction could lead to several issues for patients taking losartan:
- Altered Therapeutic Efficacy: The reduction in the formation of the more potent EXP3174 metabolite could decrease the overall blood pressure-lowering effect of losartan, despite a higher concentration of the parent drug.
- Increased Risk of Hypotension: Quercetin itself has been shown to have blood pressure-lowering effects, especially in hypertensive individuals. Combining quercetin with a powerful antihypertensive drug like losartan could lead to an additive effect, increasing the risk of dangerously low blood pressure (hypotension).
- Monitoring Challenges: The altered metabolism makes it difficult for healthcare providers to accurately predict the drug's effect and potential side effects. Close monitoring of blood pressure is essential.
Precautions for Co-administration
Given the potential for interaction, combining quercetin and losartan should be done only under strict medical supervision. Here are key points for patients to consider:
- Inform your doctor: Always tell your healthcare provider about all supplements, herbal remedies, and over-the-counter medications you are taking. This includes quercetin.
- Monitor blood pressure: Regularly monitor your blood pressure at home and report any significant changes to your doctor.
- Watch for side effects: Be aware of symptoms of hypotension, such as dizziness, lightheadedness, or fainting. If these occur, contact your healthcare provider immediately.
- Consider alternatives: Discuss non-interacting alternatives with your doctor if you wish to continue using quercetin.
Comparison of Losartan's Effects with and without Quercetin
| Feature | Losartan Alone | Losartan + Quercetin (as per animal studies) |
|---|---|---|
| Losartan Levels (AUC/Cmax) | Normal therapeutic range | Significantly increased plasma concentration |
| Active Metabolite (EXP3174) Levels | Normal therapeutic range | Significantly decreased plasma concentration |
| Metabolism | Primarily via CYP2C9 and CYP3A4 | Inhibited due to quercetin's effect on CYP enzymes |
| Drug Absorption | Standard absorption profile | Increased absorption due to P-glycoprotein inhibition |
| Antihypertensive Effect | Predictable and sustained | Potentially altered or diminished due to reduced active metabolite; risk of additive blood pressure-lowering effect from quercetin |
| Potential Risks | Standard side effects | Higher risk of hypotension; altered therapeutic response |
Conclusion
Preclinical evidence indicates that quercetin interacts with losartan by inhibiting key metabolic enzymes (CYP2C9 and CYP3A4) and the drug transporter P-glycoprotein. This interference can increase losartan levels while decreasing the concentration of its active metabolite, potentially compromising therapeutic efficacy and increasing the risk of hypotension. Given the complexity of this interaction and the limited human data, caution is advised. Patients should not combine quercetin supplements with losartan without consulting a healthcare professional to ensure proper blood pressure management and safety.
For more detailed information on losartan's pharmacokinetics, refer to the NCBI Bookshelf Losartan entry.
