Grapefruit and Methotrexate Interaction
No Clinically Significant Interaction
There is no documented interaction between grapefruit juice and methotrexate. Unlike cyclosporine and other immunosuppressants metabolized by cytochrome P450 3A4, methotrexate is primarily eliminated through the kidneys (85% renal excretion) and does not undergo significant hepatic metabolism via the CYP3A4 pathway that grapefruit juice inhibits 1.
Why This Matters
Grapefruit Affects Different Drugs
- Grapefruit juice inhibits intestinal CYP3A4 enzymes, increasing bioavailability of drugs metabolized through this pathway 2, 3
- This interaction is clinically significant for cyclosporine, where patients must completely avoid grapefruit and grapefruit juice 1
- The effect can be dramatic, with median increases in drug concentrations exceeding 70% for certain calcium channel blockers and immunosuppressants 2
Methotrexate's Different Metabolism
- Methotrexate is eliminated primarily through renal tubular secretion, not hepatic CYP450 metabolism 1
- The drugs that interact with methotrexate do so by interfering with renal secretion (NSAIDs, penicillins, sulfamethoxazole) or by displacing it from albumin binding 1
- No guidelines or studies identify grapefruit as a concern with methotrexate therapy 1, 4
Actual Methotrexate Drug Interactions to Monitor
High-Risk Interactions
- Drugs interfering with renal secretion: NSAIDs, penicillins, sulfamethoxazole, probenecid, and colchicine can decrease methotrexate elimination and increase toxicity risk 1
- Folic acid antagonists: Trimethoprim should be avoided as it compounds methotrexate's antifolate effects 1, 4
- Hepatotoxic drugs: Alcohol, statins, leflunomide, retinoids, azathioprine, and minocycline require caution due to additive liver toxicity 1
Critical Monitoring Parameters
- Complete blood count and platelets every 2-4 weeks initially, then every 1-3 months 1, 4
- Liver function tests monthly 1, 4
- Renal function (BUN, creatinine) every 2-3 months 1, 4
- Folic acid supplementation 1-5 mg daily (except on methotrexate dosing day) to reduce toxicity 1, 4
Common Pitfall
Do not confuse methotrexate with cyclosporine or other CYP3A4-metabolized immunosuppressants where grapefruit avoidance is mandatory 1. The renal elimination pathway of methotrexate makes it fundamentally different from drugs affected by grapefruit juice 1.