Summary

Verapamil significantly increases rapamycin (sirolimus) blood levels by inhibiting CYP3A4 metabolism, potentially leading to enhanced immunosuppression and increased risk of toxicity. This interaction requires careful monitoring and possible dose adjustments of rapamycin.

Introduction

Rapamycin (sirolimus) is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat certain cancers. It belongs to the mTOR inhibitor class of drugs. Verapamil is a calcium channel blocker commonly prescribed for hypertension, angina, and certain arrhythmias. Both medications are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system, which forms the basis of their significant drug interaction.

Mechanism of Interaction

The interaction between rapamycin and verapamil occurs through competitive inhibition of the CYP3A4 enzyme system. Verapamil acts as a potent CYP3A4 inhibitor, reducing the hepatic metabolism of rapamycin. This results in decreased clearance and increased bioavailability of rapamycin, leading to elevated plasma concentrations. Additionally, verapamil may inhibit P-glycoprotein transport, further contributing to increased rapamycin exposure. The magnitude of this interaction can result in 2-3 fold increases in rapamycin blood levels.

Risks and Symptoms

The primary clinical risk of this interaction is rapamycin toxicity due to elevated drug levels. Potential adverse effects include severe immunosuppression with increased infection risk, delayed wound healing, bone marrow suppression, hyperlipidemia, and nephrotoxicity. Patients may experience symptoms such as mouth ulcers, diarrhea, thrombocytopenia, and elevated serum creatinine. In transplant patients, while rejection risk may decrease due to enhanced immunosuppression, the overall risk-benefit ratio shifts unfavorably due to increased toxicity potential.

Management and Precautions

When concurrent use is necessary, rapamycin doses should be reduced by 50-75% with initiation of verapamil therapy. Frequent monitoring of rapamycin trough levels is essential, with target levels potentially requiring adjustment. Complete blood counts, liver function tests, and renal function should be monitored more frequently. Consider alternative calcium channel blockers with less CYP3A4 inhibition potential, such as amlodipine or nifedipine. If verapamil is discontinued, rapamycin doses may need to be increased gradually while monitoring drug levels. Patients should be educated about signs of rapamycin toxicity and advised to report any concerning symptoms promptly.

Rapamycin interactions with food and lifestyle

Rapamycin should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase rapamycin blood levels by up to 35%, while the timing and fat content of meals can cause variable drug absorption. Grapefruit juice should be avoided as it can increase rapamycin blood levels and potentially lead to increased side effects. Patients should maintain consistent dietary habits and timing of meals when taking rapamycin to ensure stable drug levels.

Verapamil interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking verapamil as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance verapamil's blood pressure-lowering effects and increase the risk of dizziness, fainting, and falls. High-fiber foods or fiber supplements may reduce verapamil absorption when taken at the same time, so it's recommended to separate their administration by at least 2 hours.