methotrexate and fluconazole

Fluconazole inhibits the hepatic enzymes CYP2C9 and CYP3A4, which are involved in methotrexate metabolism. It also inhibits organic anion transporters (OAT1 and OAT3) in the renal tubules, reducing methotrexate clearance and increasing its plasma concentrations.

Increased methotrexate exposure can lead to severe toxicity, including bone marrow suppression, mucositis, hepatotoxicity, and acute kidney injury. The risk is highest in patients receiving high-dose methotrexate or with pre-existing renal impairment.

Avoid concurrent use if possible. If unavoidable, reduce the methotrexate dose and monitor closely. Monitor full blood count, liver and renal function, and methotrexate plasma levels, with dose adjustment as needed.

Well-established interaction; multiple case reports and pharmacokinetic studies demonstrate increased methotrexate levels with fluconazole.